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This experiment determined the effects of transplantation of fetal hippocampus on the ability of male rats with hippocampal lesions to acquire versions of a radial arm maze that depended on either extramaze cues or intramaze cues for solution. Rats receiving transplants took significantly more trials than control rats to emit three consecutive errorless trials in the extramaze cue (spatial) variation of the maze. Rats with just hippocampal lesions never differed from any other group. No differences in this measure were found for the intramaze cue condition. Rats receiving transplants made more repeat entries into reinforced arms in both versions of the maze than control rats and more reentries into neverbaited arms in the spatial maze. Rats with hippocampal lesions failed to differ from any other group on this measure in the spatial maze, but were different from normal rats in the intramaze cue maze. These data suggest that in some tasks transplants of fetal tissue lead to greater behavioral impairment than lesions alone.

Debate continues on the merits of strictly limiting alcohol consumption during all of pregnancy, and whether “safe” consumption levels and/or times exist. Only a relatively few experimental studies have been conducted that limit the timing of exposure to specific events during development and the exposure level to one that might model sporadic, incidental drinking during pregnancy. In the present study, the effects of two acute gavage exposures to low and moderate levels of ethanol (peak blood ethanol concentrations (BEC) of 104 and 177 mg/dl, respectively) either during gastrulation on gestational day (GD) 7 (at GD7:0 h and GD7:4 h) or during neurulation on GD8 (at GD8:6 h and GD8:10 h) on the spatial learning and memory abilities of adult mice in the radial arm maze (RAM) were examined. Mice were selected from a prenatal ethanol exposure (PAE) cohort that had been tested as neonates for their sensorimotor development (Schambra et al., 2015) and as juveniles and young adults for open field activity levels and emotionality (Schambra et al., 2016). Mice exposed on either of the two gestational days to acute, low or moderate levels of ethanol were deficient in overall performance in the RAM in adulthood. Importantly, mice in ethanol exposed groups took longer to reach criterion in the RAM, and many mice in these groups failed to do so after 48 trials when testing was terminated. Exposure to a low level of ethanol on either GD7 or GD8, or a moderate level on GD7, resulted in significant impairment in spatial reference (long-term) memory, while only mice exposed on GD7 to the low level of ethanol were significantly impaired in spatial working (short-term) memory. Mice exposed to the low ethanol level on either day had significantly shorter response latencies, which may reflect impairment of processes related to response inhibition or executive attention in these mice. For all measures, distributions of individual scores revealed a relatively small subset of mice in each PAE group who scored well outside the range of the control group, which skewed the population distributions to varying degrees in the direction of worse performance for the PAE groups. Overall the data suggest that after acute, low level ethanol exposure early in gestation, the likelihood that an individual mouse embryo experienced measureable ill-effects due to the exposure was rather low, but in a few of the embryos, damage occurred that resulted in significant deficits in later performance. The overall characteristics of our cohort of PAE mice, including delayed sensorimotor development, mild hypoactivity and increased emotionality, as shown in previous studies, together with deficits in spatial learning and memory as shown here, resemble those in a subset of human Fetal Alcohol Spectrum Disorder (FASD) diagnoses, specifically ADHD-Inattentive type (ADHD-I) and/or Sluggish Cognitive Tempo (SCT). Although possible correspondences between mechanisms underlying PAE-induced deficits in mice and those operating in humans remain undefined, further study with this mouse PAE model may ultimately help advance understanding of the causes of these conditions in affected children. This study highlights the possibility of risk associated with low to moderate sporadic alcohol consumption during the first month of human pregnancy.

Indiana University-Purdue University Indianapolis (IUPUI) / Nicotine use among individuals with schizophrenia occurs at extremely high rates. The prevailing theory is that individuals with schizophrenia smoke as a form of self-medication to ameliorate sensory and cognitive deficits. However, these individuals also have enhanced rates of addiction to several drugs of abuse and may therefore smoke as a result of enhanced addiction liability. The experiments described herein explored these two hypotheses by assessing the effect that nicotine has on working memory, addiction vulnerability (locomotor sensitization and self-administration), and nicotinic acetylcholine receptor (nAChR) expression as well as the developmental expression of these characteristics in the neonatal ventral hippocampal (NVHL) neurodevelopmental animal model of schizophrenia. The results from these studies indicate that NVHLs had working memory impairments in both adolescence and adulthood, with nicotine having a negligible effect. Additionally, NVHLs displayed enhanced locomotor sensitization to nicotine which emerged in adulthood as well as an enhanced acquisition of nicotine self-administration, administering more nicotine overall. These behavioral differences cannot be attributed to nAChR expression as nicotine upregulated nAChR to a similar extent between NVHL and SHAM control animals. These data indicate that the enhanced rates of nicotine use among individuals with schizophrenia may occur as a result of an enhanced vulnerability to nicotine addiction.

Rats were administered nicotine (0.3 mg/kg) for 11 consecutive days before and after an electrolytic medial frontal cortex lesion. Behavioral testing was arranged so that the rats were tested on the RAM 1 day after drug administration followed by behavioral testing on the MWT 19 days after drug treatment, or tested on the MWT 1 day after drug administration followed by testing on the RAM4 days after drug treatment. Results of MWT testing showed that regardless of the drug/behavioral testing interval, lesioned rats given nicotine demonstrated enhancement relative to saline-treated animals. Results of RAM testing showed that nicotine improved performance in non-lesioned rats compared to non-lesioned rats given saline. Four days after drug administration, nicotine improved performance in lesioned rats to levels of non-lesioned rats regardless of drug treatment. A second experiment was implemented to determine if the previous training on the MWT affected performance on the RAM.

兒茶酚胺類神經傳遞系統被認為與包括記憶學習等行為功能有很重要的關連，在記憶多元化理論的假設下，該神經系統與其它者對於特定記憶學習行為應有再確認之必要。過去對於空間性記憶的研究，其相關支持證據所依據之實驗操弄泰半集中在海馬迴系統上。但仍有部份研究指出大腦中的其他區域可能同樣與一般記憶的運作有密切的關連。特別是兒茶酚胺系統所在之紋狀總體組織部位（包括尾狀核與阿控博核），vP A僅與感覺接受、運動反應及增強作用等機制有關外，同時可能也扮演影響記憶表現的重要因子。本研究使用慾求性的八角迷津為工具，藉其地點學習與反應學習這兩種不同的迷津作業，及利用兒茶酚胺類的藥物或神經毒素，探討相關的記憶習得與記憶保持歷程所造成的影響。實驗的操弄包括：(1) 迷津作業之地點學習與反應學習以探討這兩種記憶之行為機制。(2) 記憶習得與記憶保持階段以瞭解這兩種迷津作業所引發記憶之全部歷程。(3) 中樞（阿控博核或尾狀核）神經毒素之破壞以及周邊藥物注射以確認兒茶酚胺類藥物對於記憶之神經藥理機制。本研究分為兩大實驗進行，實驗一以地點學習為主，實驗二以反應學習為主。實驗結果可以簡單歸納如下：(1) 兩 種學習作業的記憶策略有不同的習得歷程及需要不同的處理訊息。(2) 在迷津學習前用神經毒素 6-OHDA 破壞尾狀核或阿控博核，皆會影響地點記憶的習得，但對於反應記憶的習得，則需要同時破壞尾狀核及阿控博核才有類似的干擾效果。(3) 相對於神經毒素 6-OHDA的干擾效果，DSP-4皆不影響地點學習與反應學習的習得歷程。(4) 在記憶保持階段中，周邊注射兒茶酚胺類藥物 d-amphetamine、haloperidol 與 propranolol均會干擾地點記憶的提取，但卻不影響反應記憶的提取表現。(5) 於地點記憶與反應記憶習得後，給予尾狀核加阿控博核的雙側 6-OHDA 注射均不影響這兩種記憶的提取表現。實驗結果顯示兒茶酚胺類神經傳導系統對於記憶功能具有明顯的影響，其中紋狀體扮演了相當重要的角色。相對於不影響記憶提取之歷程，紋狀體的破壞對記憶習得歷程有阻滯之效果，其內部之尾狀核與阿控博核分別依不同之迷津作業具有相異之效果，且多巴胺系統較正腎上腺素系統明顯的參與了影響效果，這些結果顯示兒茶酚胺類神經傳導系統與記憶表現有密切的關連。 / Catecholamine (CA) neurotransmission systems are critically involved in the control of many behavioral functions including learning and memory. The role of CA in mediating learning and memory is recently focused on the basis of multiple memory hypothesis. In addition to the previous finding of spatial memory relevant to the hippocampal areas, the striatum containing the caudate nucleus and the nucleus of accumbens is thought to be important for executing the learning and memory function. By the use of radial arm maze (RAM), the present study examined the effects of CA related neurotoxins and drugs on the acquisition and retention stages of both place and response tasks. Two major parts of experiments were designed to reveal the neurobehavioral mechanisms for the place and response tasks of RAM. Food-deprivated rats were trained to enter the arms baited with chocolate in the eight-arm maze. Specific four arms were baited for each rat in the place task, while randomly selected four arms each cued with a piece of sand paper on the arm entrance were baited for the rat in the response task.The results can be summarized as followings. (1) Differen behavioral processes were shown in performing the place and response tasks. (2) The acquisition deficits were significantly produced by 6-hydroxydopamine (6-OHDA) lesion on either caudate or accumbens for the place task, whereas the acquisition of response task was only impaired by 6-OHDA lesions of both caudate and accumbens together. (3) In contrast to 6-OHDA, adrenergic neurotoxin DSP-4 did not significantly affect subjects to acquire either task. (4) During the retention stage, the performance of place task was significantly disrupted by d-amphetamine, haloperidol, or propranolol. However, this was not the case for the retrieval of response task. (5) Once acquired, neither place nor response task performamce could be influenced by 6-OHDA simultaneously administered on the caudate and accumbens areas.Taken together, these data collected from RAM support the idea that the striatal CA is essential for the leraning and memory. Shift of the CA neurotransmission function induced by either 6-OHDA lesions or relevant drugs can disrupt the RAM behavior, which impairment to be detectable is depended on the learning task itself as well as the time of a specific task being leraned.

本研究以神經毒素ibotenic acid破壞不同尾核區域以及鋰鹽去價值程序為操弄變項，觀測此兩種實驗操弄對於大鼠之迷津行為之影響，進而探討標誌系統之行為內涵及神經機制。實驗所採用的作業為線索學習作業以及自我中心作業，分別代表標誌系統下的線索導引策略及體位導向策略。實驗一及實驗二在於檢驗尾核功能缺損對於大鼠迷津行為之影響，從探測嘗試發現大鼠在線索學習的行為表現需依賴砂紙線索的導引，而在自我中心作業之行為則不以環境刺激為依據（實驗一A、二A），顯示大鼠在各迷津作業的行為符合標誌系統的運作原則。神經機制之操弄結果顯示在記憶習得階段，尾核破壞之受試在線索學習作業上的表現並沒有顯著變差，尾核功能缺損並未導致學習的延宕或阻斷，其進步的速度仍與控制組相同（實驗一B）。相較於線索學習作業，尾核破壞之受試在自我中心作業上的表現則明顯變差，幾乎沒有進步的趨勢（實驗二B）。而在記憶保持階段，不管是線索學習作業或自我中心作業之表現皆會因尾核破壞而顯著變差（實驗一C、二C）。實驗三及實驗四則利用鋰鹽去價值程序降低食餌之誘因價值，觀測大鼠行為有無相對應改變。結果發現去價值程序的操弄只會影響到大鼠在自我中心作業的行為表現（實驗四），而不影響其在線索學習作業之行為（實驗三）。由此可知，兩種迷津作業所形成的記憶表徵是不同的，自我中心學習歷程會將增強物表徵在聯結單位中，而線索學習之習得歷程則不會。綜合上述實驗結果，標誌系統下確實有兩個不同空間行為機制，一個為線索導引策略，另一個為體位導向策略，雖皆受到尾核的調節，但調節的程度是不同的。不管是記憶習得或保持階段，尾核在體位導向策略的運作中皆扮演重要的角色，而在線索導引策略只參與了記憶保持歷程的運作。另外，兩個空間行為機制在學習內涵上也不盡相同，以線索導引策略為依據之空間行為會形成刺激反應(S-R)的聯結型態，而以體位導向策略為依據之空間行為則會形成反應及增強物(R-S*)聯結。 / This study investigated the neurobehavioral mechanisms of taxon system of spatial memory through manipulating lesions of subareas in the caudate nucleus by ibotenic acid and lithium chloride (LiCl)-induced reward devaluation. With respect to behavioral measurement in an eight-arm radial maze, a cue learning task and an egocentric task were used for testing the guidance and orientation hypotheses of taxon system, respectively. Data from probing procedures showed that the performance of rats in the cue learning task was impaired when the cue was removed, but the performance in the egocentric task was not affected by changing the context (Experiments 1A and 2A). These results indicate that behavior reactions in two tasks are corresponding to those two operational principles of taxon system. In terms of the acquisition, deficits were significantly produced by the lesion of the dorsomedial caudate on egocentric task, while the ibotenate lesions did not affect cue learning task (Experiments 1B and 2B). For retention test, the performances in both cue learning and egocentric tasks were impaired by dorsomedial caudate lesion, no such impairment was observed from dorsolateral and posterolateral caudate lesions (Experiments 1C and 2C). In the third and fourth experiments, LiCl devaluation procedure was employed to lower the reward value of the bait in the maze. This manipulation significantly impaired the performance of egocentric task but not that of the cue learning task. These results indicate that the memory representations in the two tasks used in the present study are different. The memory representation in the egocentric task contains the reinforcer, whereas that in the cue learning task is not necessarily relevant to the reinforcer. In conclusion, the guidance and orientation hypotheses can be differentiated as behavioral mechanisms existing in the taxon system of spatial memory. Although the caudate nucleus is critically important for the operation of both hypotheses, the degrees of this brain site to get involved are different. The caudate nucleus participates in the acquisition and retention of orientation hypothesis, but only in the retention of guidance hypothesis. In addition, behavioral performance of the spatial memory using guidance hypothesis is based on forming the association of stimulus and response (S-R), while that using orientation hypothesis is based on forming the association of response and reinforcer (R-S*).