It is suggested that the hippocampal formation is essential to spatial representations by flexible encoding of diverse information during navigation, which includes not only externally generated sensory information such as visual and auditory sensation but also ideothetic information concerning locomotion (i.e., internally generated information such as proprioceptive and vestibular sensation) as well as information concerning reward. In the present study, we investigated how various types of information are represented in the hippocampal formation, by recording hippocampal complex-spike cells from rats that performed three types of place learning tasks in a circular open field with the use of intracranial self-stimulation as reward. The intracranial self-stimulation reward was delivered in the following three contexts: if the rat 1) entered an experimenter-determined reward place within the open field, and this place was randomly varied in sequential trials; 2) entered two specific places, one within and one outside the place field (an area identified by change in activity of a place neuron); or 3) entered an experimenter-specified place outside the place field. Because the behavioral trails during navigation were more constant in the second task than in the first task, ideothetic information concerning locomotion was more relevant to acquiring reward in the second task than in the first task. Of 43 complex-spike cells recorded, 37 displayed place fields under the first task. Of these 37 place neurons, 34 also had significant reward correlates only inside the place field. Although reward and place correlates of the place neuron activity did not change between the first and second tasks, neuronal correlates to behavioral variables for locomotion such as movement speed, direction, and turning angle significantly increased in the second task. Furthermore, 6 of 31 place neurons tested with the third task, in which the reward place was located outside the original place field, shifted place fields. The results indicated that neuronal correlates of most place neurons flexibly increased their sensitivity to relevant information in a given context and environment, and some place neurons changed the place field per se with place reward association. These results suggest two strategies for how hippocampal neurons incorporate an incredible variety of perceptions into a unified representation of the environment: through flexible use of information and the creation of new representations.

Predicting reward is essential in learning approach behaviors. Dopaminergic activity has been implicated in reward, movement, and cognitive processes, all essential elements in learning. The nucleus accumbens (NAc) receives converging inputs from corticolimbic information-processing areas and from mesolimbic dopamine neurons originating in the ventral tegmental area. Previously, we reported that in mice, a dopamine D2 receptor knockout (D2R-KO) eliminated the prereward inhibitory response, increased place-field size of NAc neurons, and reduced locomotor activity without marked change in intracranial self-stimulation (ICSS) behavior. The present study investigated the specific contribution of dopamine D1 receptor (D1R) in mediating reward, locomotor activity, and spatial associative processes and in regulating NAc neural responses. In contrast to D2R-KO animals, here we find D1R-KO in mice selectively eliminated the prereward excitatory response and decreased place-field size of NAc neurons. Furthermore, D1R-KO impaired ICSS behavior, seriously reduced locomotor activity, and retarded acquisition of a place learning task. Thus, the present results suggest that D1R may be an important determinant in brain stimulation reward (ICSS) and participates in coding for a type of reward prediction of NAc neurons and in spatial learning.dopamine receptor ͉ nucleus accumbens ͉ spatial learning D opaminergic systems innervate the hippocampal formation (HF), prefrontal cortex, amygdala (AM), and ventral striatum and mediate cognitive processes of working memory and learning (1-6). The nucleus accumbens (NAc) is reliably linked to motivation, locomotion, reward-related processes, and some cognitive functions (1,3,(7)(8)(9). It receives excitatory glutamatergic input from the prefrontal cortex, HF, and AM, as well as a dense converging dopaminergic innervation from the ventral tegmental area (3, 10, 11). Thus, NAc neurons are positioned to recognize context-driven patterns of activation and to relay this information to planning and motor executive systems for appropriate behavioral responses (1,3,7,8,12). Dopamine has profound effects on behavior as highlighted in previous studies (13-16). Nevertheless, the contribution of dopamine D1 receptor (D1R) in assessing reward information at neural level and its link to behaviors such as spatial associative learning remains to be specified. In the present study, we used knockout mice lacking D1R (D1R-KO) and their wild-type (WT) littermates to examine the contribution of this receptor in mediating reward, locomotion, and spatial learning and in regulating neural responses to prediction of reward. These mice were tested for their ability to perform several spatial tasks, including random reward place search task (RRPST) and place learning task (PLT), by using intracranial self-stimulation (ICSS) as rewards (15). To investigate the involvement of D1R functions in reward processing and spatial associative processes, we recorded neural activity from the NAc of D1R-KO mice and their WT litte...

The aim of the present study was to establish a progressive steatohepatitis mouse model because few reported animal models of non-alcoholic steatohepatitis (NASH) show the progression from fatty liver to steatohepatitis. C57BL/6N mice were fed a high-fat diet (HFD) to develop obesity and were either administered carbon tetrachloride (CCl4 ) eight times (0.05 mL/kg, s.c., once, followed by 0.1 mL/kg, s.c., seven times) or not. Serum parameters and hepatic histopathology were examined. In a separate experiment, CCl4 was administered subcutaneously from 0 to eight times to HFD-fed obese mice to investigate progressive changes. Markers of oxidative stress, inflammation and apoptosis, as well as histopathological changes in the liver, were analysed. The HFD-fed obese mice showed fatty liver but not steatohepatitis. In contrast, HFD-fed mice administered CCl4 eight times showed histopathological features of steatohepatitis (fatty liver, inflammation, hepatocellular ballooning and fibrosis) and increased serum alanine aminotransferase levels. However, the multiple administration of CCl4 to obese mice reduced the ratio of reduced glutathione to oxidized glutathione, superoxide dismutase activity and mitochondrial DNA copy number, leading to the development of chronic oxidative stress, increased numbers of apoptotic cells and increased levels of both tumour necrosis factor-α and transforming growth factor-β mRNA. The resulting inflammation led to increased hydroxyproline content in the liver and fibrosis. The present study demonstrates that multiple administration of CCl4 to HFD-fed obese mice induces chronic oxidative stress that triggers inflammation and apoptosis and leads to the development of fibrosis in the liver, resulting in progression from fatty liver to steatohepatitis. This murine model will be useful in the research of hepatic disorders.

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