Neuroscience
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Neuroligin 1 (NLGN1) is a postsynaptic adhesion molecule that determines N-methyl-d-aspartate receptor (NMDAR) function and cellular localization. Our recent work showed that Nlgn1 knockout (KO) mice cannot sustain neuronal activity occurring during wakefulness for a prolonged period of time. Since NMDAR-dependent neuronal activity drives an important vascular response, we used multispectral optical imaging to determine if the hemodynamic response to neuronal stimulation is modified in Nlgn1 KO mice. ⋯ Moreover, Nlgn1 mutant mice showed an earlier oxyhemoglobin peak response that tended to return to baseline faster than in WT mice. Analysis of the time course of the hemodynamic response also showed that HET mice express a faster dynamics of cerebrovascular response in comparison to WT. Taken together, these data are indicative of an altered immediate response of the brain to peripheral stimulation in Nlgn1 KO mice, and suggest a role for NLGN1 in the regulation of cerebrovascular responses.
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Recent research suggests an involvement of pro-opiomelanocortin (POMC) gene products (e.g., beta-endorphin) in modulating cocaine-induced reward and addiction-like behaviors in rodents. In this study, we investigated whether chronic "binge" cocaine and its withdrawal altered POMC gene expression in the brain of rats. Male Fischer rats were treated with two different chronic (14-day) "binge" pattern cocaine administration regimens (three injections at 1-h intervals, i.p.): steady-dose (45mg/kg/day) and escalating-dose (90mg/kg on the last day). ⋯ In contrast, after acute (1-day) withdrawal from chronic "binge" escalating-dose regimen, but not steady-dose regimen, there were increased hypothalamic POMC mRNA levels that persisted into 14days of protracted withdrawal. To study the role of the endogenous opioid systems in the cocaine withdrawal effects, we administered a single naloxone injection (1mg/kg) that caused elevated POMC mRNA levels observed 24h later in cocaine naïve rats, but it did not lead to further increases in cocaine-withdrawn rats. Our results suggest that during withdrawal from chronic "binge" escalating-dose cocaine: (1) there was a persistent increase in hypothalamic POMC gene expression; and (2) hyposensitivity of the POMC gene expression to naloxone indicates altered opioidergic tone at or above the hypothalamic level.
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Diabetes mellitus (DM) is a major risk factor for stroke and it exacerbates tissue damage after ischemic insult. Diabetes is one of the important causes of the progression of white matter lesion, however, the pathological mechanisms remain unclear. The present study evaluated the influences of type 2 DM on ischemic subcortical white matter injury and the recruitment of oligodendrocyte progenitor cells (OPCs) under chronic cerebral hypoperfusion using type 2 diabetic (db/db) mice. ⋯ Finally, we assessed the survival of 5-bromo-2'-deoxyuridine (BrdU)-positive proliferating cells in ischemic white matter, and found significantly poorer survival of BrdU/PDGFRα-positive OPCs or BrdU/GST-pi-positive OLGs in the db/db mice compared to the db/+ mice in the white matter after BCAS. Our findings suggest that the type 2 DM mice exhibited more severe white matter injury 8 weeks after chronic ischemia. Decreased proliferation and survival of OPCs may play an important role in the progression of white matter lesions after ischemia in diabetics.
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Chronic exposure to the stress hormone corticosterone (CORT) is known to alter plasticity within hippocampal and amygdalar circuits that mediate fear learning and memory. The purpose of this experiment was to clarify the effects of chronic CORT on Pavlovian fear conditioning, which is dependent on intact hippocampal and amygdalar activity. In particular, we assessed whether the effect of chronic CORT on fear learning and memory is influenced by two factors-the dose of CORT and the order in which rats are tested for freezing to context versus tone cues. ⋯ We also found an order effect in that the effects of CORT on freezing were greater on the second day of testing, regardless of whether that testing was to context or tones cues. This order effect may be due to a lack of extinction in the CORT rats. Overall, these results suggest a relationship between stress intensity and testing conditions that should be taken into account when assessing the effect of stress on fear memories.
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Altered expression of neuronal cytoskeletal proteins are known to play an important role in hyper-excitability of neurons in patients and animal models of epilepsy. Our previous work showed that cell division cycle 42 GTP-binding protein (Cdc42), a small GTPase of the Rho-subfamily, is significantly increased in the brain tissue of patients with temporal lobe epilepsy (TLE) and in the brain tissues of the epileptic model of rats. However, whether inhibition of Cdc42 can modify epileptic seizures has not been investigated. ⋯ Whole-cell patch-clamp recording on CA1 pyramidal neurons in hippocampal slices from pilocarpine-induced epileptic model demonstrated that ML141 significantly inhibits the frequency of action potentials (APs), increases the amplitude and frequency of miniature inhibitory postsynaptic currents (mIPSCs), and increases the amplitude of evoked inhibitory postsynaptic currents (eIPSCs). However, ML141 did not have an impact on the miniature excitatory postsynaptic currents (mEPSCs). Our results are the first to indicate that Cdc42 plays an important role in the onset and progression of epileptic-seizures by regulating synaptic inhibition.