The role of the pedunculopontine tegmental nucleus (PPTg) in motivation and cognitive functions is controversial. In order to clarify the involvement of this nucleus in learning, rats with N-methyl-D-Aspartate (NMDA) lesions to the PPTg were tested on the acquisition of a delayed non-matching to position task (DNMP) performed in a T-maze. Unlike sham-lesioned rats, animals with PPTg lesions did not learn the task. Analysis of the behavior displayed by the lesions animals, however, suggested that these rats suffered from elevated emotionality or arousal, rather than from learning deficits. This hypothesis was confirmed by demonstrating that the anxiolytic compound diazepam (1 mg/kg) normalized the performance of the PPTg-lesioned rats on the DNMP task and reduced the indices of anxiety displayed by animals with PPTg lesions when tested on the elevated plus maze. / These results suggested the possibility that the motivational impairments reported to be induced by PPTg lesions, could also be an artifact of lesion-induced elevation of anxiety or arousal. Thus, in order to verify this hypothesis, it was tested whether diazepam would modify the expression of conditioned place preference (CPP) to morphine and amphetamine in animals with NMDA-induced lesions to the PPTg. Diazepam reversed the effects of the lesion on a morphine CPP but not on an amphetamine CPP. A series of experiments, aimed at characterizing the effects of diazepam on morphine and amphetamine reinforcement in normal rats, showed that diazepam, either systemic or injected in the nucleus accumbens, blocks the reinforcing effects of amphetamine but has no effect on the reinforcing effects of morphine. These results suggest that impairments in CPP learning caused by PPTg lesions do not result from motivational deficits, but are caused by elevated emotionality or abnormal arousal.

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Working memory is the cognitive capacity for temporarily holding information in mind for processing or use, and supports most of our actions and behaviors. Although activity in the rodent prefrontal cortex (PFC) is necessary for successful rodent spatial working memory utilization, rodent spatial working memory tasks do not always evoke robust PFC delay encoding of retrospective spatial information. We hypothesized that, like in nonhuman primates (NHPs), increasing spatial optionality might facilitate the detection of retrospective spatial encoding in the PFC. We therefore used an automated 8-arm radial maze to implement a novel match-to-sample rodent spatial working memory task with seven options on each trial, and recorded calcium activity in PFC neurons during task performance. We found that, during the delay phase of the task, PFC neurons indeed encoded retrospective spatial representations of the arm visited in the preceding sample phase, at both single-cell and population levels, in a distributed manner. Also, in accordance with recent NHP work, these representations were evident in considering dynamic, heterogenous neural activity, and in considering a low-dimensional subspace, where time-invariant retrospective spatial information could be decoded. Thus, this work reveals that in rodents, freely-moving, spatially-demanding behavioral paradigms can evoke distributed spatial working memory representations in the prefrontal cortex, with reasonable similarity to the working memory representations observed in nonhuman primates.

Indiana University-Purdue University Indianapolis (IUPUI) / Despite warnings about the dangers of drinking during pregnancy, little progress has been made in reducing alcohol drinking among women of childbearing age. Even after the recognition of pregnancy, 15% of women continue to drink, 3% of which admit to binge drinking. Because we cannot stop women from drinking during pregnancy, and many children with fetal alcohol spectrum disorders (FASD) are adopted, there is a significant need to develop postnatal interventions that can improve the long-term outcome of children adversely affected by prenatal alcohol exposure. This thesis aims to evaluate one promising new treatment in the rehabilitation or rescue of specific learning deficits long after the damage has occurred. The treatment evaluated herein (40µg D-NAP + 40µg D-SAL) has long been used in the prevention of the detrimental effects of long-term and binge-like alcohol exposures in rodent models of fetal alcohol syndrome and FASD. Until recently this peptide treatment had only been shown to be effective in preventing some of the consequences of alcohol exposure when administered concurrently with the prenatal alcohol exposure. A recent report by Incerti and colleagues (2010c), however, reported that these peptides could completely reverse a profound spatial learning deficit induced by one episode of a heavy binge-like alcohol exposure (5.9g.kg in a single intraperitoneal injection) on gestational day 8 (G8) in C57BL/6 mice. In that report, the peptide treatment was administered starting in late adolescence, beginning three days prior to and throughout water maze training, and the profound deficits in their alcohol-placebo group were completely eliminated in the alcohol-peptide group. There are currently no FDA-approved treatments for FASD. An effective treatment for the cognitive and behavioral dysfunctions suffered by the 1% of people born today could potentially improve the lives of millions of children and adults. The first aim of this thesis was to determine whether the peptide treatment could reverse the significant spatial learning deficits we have demonstrated in adult C57BL/6 mice given high-dose binge-like alcohol exposure (2.5 g/kg in each of two intraperitoneal injections separated by two hours) on postnatal day (P)7. When administered three days prior to and throughout water maze testing (P67-76), the peptide treatment had no effect on spatial learning. The second aim sought to determine whether the same peptide treatment could reverse water maze spatial learning deficits in G8 binge-like exposure models, as reported by Incerti et al. (2010c). For this analysis, the first study used a different binge-like alcohol exposure model that is more commonly used than that employed by the Incerti et al. (2010c) study, namely administration of 2.8g/kg in each of two intraperitoneal injections separated by four hours (Sulik et al., 1981). This model has been shown to produce high peak blood alcohol concentrations and neuroanatomical aberrations in the hippocampal formation and septal regions (Parnell et al., 2009), which have been implicated in learning and memory. Surprisingly, this G8 binge-like alcohol exposure failed to produce a spatial learning deficit, undermining the usefulness of this model in evaluating the peptide effects. In direct contrast to the outcomes of Incerti et al. (2010c), the G8 Webster alcohol exposure was also unable to produce any deficits in acquisition of spatial learning in the Morris water maze. Surprisingly, neither of the heavy binge-like alcohol exposures on G8 were able to produce spatial learning deficits in the Morris water maze. The binge-like alcohol exposure on P7 did yield the expected spatial learning deficit, but the peptide treatment was unsuccessful in recovering water maze learning. These findings fail to support oral administration of 40µg D-NAP and 40 µg D-SAL as a potential therapy for postnatal alcohol-induced spatial learning deficits in adult mice.