Indiana University-Purdue University Indianapolis (IUPUI) / Alcohol-paired cues invigorate alcohol-seeking and drinking behaviors in both rodents and individuals with alcohol use disorder (AUD). Additionally, genetic susceptibility plays a key role in alcohol addiction behaviors. Alcohol preferring (P) rats model both genetic vulnerability and symptoms of AUD. The basolateral amygdala (BLA), prefrontal cortex (PFC), hippocampus (HC) and nucleus accumbens (NA) are important brain regions involved in cued alcohol seeking. These regions are interconnected and their functional connections are hypothesized to be critical in the expression of motivated behaviors. Electrophysiological recordings in these four regions were collected in P rats engaged in a cued alcohol task. Data were filtered in the theta band (5-11 Hz) and segregated by behavioral epoch. The phase locking index γ was computed and used to measure strength of phase locking between signals from any two brain regions. The cross correlation between the amplitude of two signals was used to determine directionality. PFC-NA synchrony increased after stimuli presentation and remained elevated, relative to baseline synchrony. PFC-NA synchrony was also stronger for trials in which the animal made three or more lever presses (rewarded; R), compared to trials in which the animal responded fewer than three times (not-rewarded; NR). During lever pressing, PFC-BLA, NA-HC and PFC-HC synchrony was stronger after presentation of the DS+, in R compared to NR trials. NA-HC and PFC-BLA synchrony was stronger when responses were withheld in extinction, relative to conditioning. These data inform our knowledge of how corticolimbic connections are involved in cued ethanol seeking behaviors.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第19180号 / 人健博第28号 / 新制||人健||3(附属図書館) / 32172 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 高桑 徹也, 教授 市橋 則明, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13142号 / 論医博第2142号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 野田 亮, 教授 岩田 想 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Our laboratory has invented a series of oxime acetylcholinesterase (AChE) reactivators (US Patent 9,227,937) that enter the brain, reduce time to cessation of seizure-like activities, and prevent organophosphorus compound (OP) neuropathology, not seen with the current U.S. approved AChE reactivator, pralidoxime (2-PAM). Thus, 2-PAM fails to protect the brain against damage and long-term cognitive and behavioral deficits seen in humans after OP exposure. However, the mechanisms by which these novel oximes provide central neuroprotection through preservation of neuronal cell structures from damage in a rat model are not fully understood by AChE reactivation alone. This dissertation investigated neurotoxic mechanisms of NIMP as potential targets for additional direct and indirect neuroprotection by our lead in vivo AChE reactivator, Oxime 20. Male Sprague Dawley rats exposed to NIMP experienced neurotoxic effects in areas critical to OP-induced seizure generation (e.g., hippocampus and piriform cortex) such as the inhibition of multiple serine hydrolases (i.e., fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL)), necrotic cell death evident by increased necrotic receptor-interacting serine/threonine-protein kinase 1 (RIPK1) levels and no apoptotic caspase-3 activity, and increased levels of neuroinflammation via elevated levels of pro-inflammatory oxylipins 4 days post lethal exposure. However, due to the lack of statistical significance, NIMP exposure did not definitively affect the subcellular location of either phosphorylated excitatory N-methyl-D-aspartate (NMDA) receptor or inhibitory γ-aminobutyric acid (GABA) receptor subunits. Results suggested that Oxime 20 therapy provided neuroprotection after NIMP exposure, such as limited reactivation of other serine hydrolase targets, significantly decreased RIPK1 levels (i.e., necrotic environment) in the hippocampus, and significantly decreased inflammatory oxylipins 4 days post-NIMP exposure. Thus, reducing OP-induced neuroinflammation might be the main contributor to the neuroprotection (i.e., neuronal cell structure preservation) previously observed in our laboratory.

The effect of transplants of either fetal hippocampal or dorsal ventricular ridge (DVR) tissue into the brains of adult male rats exposed to TMT was determined for two behavioral tasks. Administration of TMT produced deficits in acquisition and performance of an operant differential reinforcement of low response rates (DRL) schedule and learning in the Morris water maze. The fetal transplants developed well within the TMT damaged brains of the adult rats and numerous axons could be shown to cross the host transplant interface. The transplants significantly recuced the DRL deficit produced by exposure to TMT. However, the TMT-induced deficit in water maze acquisition was made significantly worse by the hippocampal transplants. The improvement in DRL performance is attributed to the effect on the host brain of an unidentified trophic substance produced by the transplants. However, this positive effect may not protect the brain sufficiently to produce recovery in tasks demanding more complex neural computations than are required to withhold lever-press responses. The transplant-induced deficit observed in some aspects of water maze acquisition and performance may be attributable to either a tumor-like deleterious effect of the mass of the transplant or to abnormal neuronal activity transmitted from the transplant to the host brain. The results of the present study, and those from other similar studies, suggest that transplants of fetal tissue may be useful in producing changes in the brain of an animal exposed to an environmental neurotoxin, but that research should be focused upon development of transplant methodology that will minimize adverse effects of the grafts.

In rat, the neonatal destruction of nigrostriatal dopamine (DA) neurons by intracerebral administration of 6-hydroxydopamine entails dramatic changes in serotonin (5-hydroxytryptamine, 5-HT) as well as DA function. Most striking is the 5-HT hyperinnervation of the adult neostriatum, associated with increases in density of various 5-HT receptor subtypes and enhanced neuronal responsiveness to the iontophoretic application of 5-HT and its 5- HT(1B/2C) and 5-HT(2A/2C) receptor agonists, m-chlorophenylpiperazine and iododimethoxyphenylaminopropane. The topographical distribution of these changes is consistent with up-regulation and/or increased production and transport of 5-HT(1B) and 5-HT(2A) receptors by the neostriatal projection neurons, as confirmed for the 5-HT(2A) receptor in a recent in situ hybridization study. It is interesting that this study has also shown that increases in both 5-HT(2A) binding and mRNA level were abolished by chronic pretreatment with the DA agonists, apomorphine and SKF 38393, suggesting a regulatory influence of DA in the expression of this 5-HT receptor. D1 receptor binding is known to be slightly reduced in the rostral neostriatum of these rats, a down-regulation apparently imputable to a reduced rate of synthesis of the receptor. In contrast, D2 receptor binding is increased throughout the DA-denervated and 5-HT-hyperinnervated neostriatum, perhaps due to some post-transcriptional modifications. Stereotyped and motor behaviors induced by systemic treatment with D1 and D2 agonists are markedly enhanced in these rats (behavioral supersensitivity), although priming is commonly required to unmask a latent D1 supersensitivity. In the case of oral activity, however, overt behavioral supersensitivity is induced by D1 as well as D2 agonists. Moreover, there is overt supersensitivity of oral activity in response to the 5-HT receptor agonist m- chlorophenylpiperazine, which is presumably imputable to 5-HT(2C) receptors and may be demonstrated even in the absence of supersensitivity to D1 receptor agonist. 5-HT adaptations, therefore, seem to play a role not only in the abnormal spontaneous behavior, but also in the behavioral supersensitivity to 5-HT as well as DA receptor agonists in these rats.

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