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Major depressive disorder (MDD) is a debilitating disorder affecting hundreds of millions of people worldwide. The etiology of the disease is unknown, and how antidepressant medications reverse depression is unclear. However, imaging and postmortem studies of MDD patients show abnormalities in several limbic areas of the brain, including the prefrontal cortex. The involvement of the ventromedial prefrontal cortex (vmPFC) in depression has been particularly intriguing, for this region demonstrates reduced metabolic activity in remission, and this reduction is unique to treatment responders. In addition, deep brain stimulation targeting the subgenual cingulate cortex in the vmPFC has been shown to be effective in treating 'treatment-resistant' patients. Furthermore, neuroanatomical studies have shown that this region projects to many downstream limbic areas implicated to play roles in MDD. I therefore hypothesized that 1) the vmPFC may be an important target of antidepressant drugs, and that 2) this region may play a role in the generation of depression-associated behaviors. To test the first hypothesis, I administered desipramine (DMI), a tricyclic antidepressant, to rats. I found that the rat vmPFC was significantly activated by DMI, whereas the dorsomedial PFC (dmPFC) was not. I also found that the drug increases neuronal activity in the nucleus accumbens, but this activation was dependent on the integrity of the vmPFC. To test the second hypothesis, I induced neuronal lesions in the rat dmPFC or vmPFC and subjected the animals to behavioral tests. I found that while lesions in both areas led to increased REM sleep, only vmPFC-lesioned animals had reduced REM latency, increased sleep fragmentation and increased forced swim test immobility. Together, these results demonstrate that the vmPFC may be an important region for both antidepressant action and the generation of depression-like behaviors.

The activity of neurons in the prefrontal cortex (PFC) may underlie working memory processes in the brain. Both the performance of working memory tasks and the activity of PFC neurons are modulated by dopamine. The goal of the present thesis was to gain insight into the neural basis of working memory by studying the PFC, and the DA system in the PFC, from both a behavioral and cellular perspective. The functional contribution of the PFC to working memory processes in the rat was assessed in Chapter 2 of the present thesis using memory-based foraging tasks on an 8-arm radial maze. The results of these studies indicated that lidocaine-induced inactivations of the PFC selectively disrupted the ability to use mnemonic information to guide foraging, but not the ability to acquire or retain such information. The ability to use mnemonic information to guide foraging was also disrupted by microinjection of a D1 but not D2 receptor antagonist into the PFC. Chapters 3-5 investigated how PFC neurons process synaptic inputs to their dendrites to produce spike output. The intrinsic membrane properties and synaptic responses at the soma and dendrites of deep layer PFC pyramidal neurons were recorded using sharp intracellular or whole-cell patch-clamp techniques in a brain-slice preparation. Different passive and active membrane properties of the soma and dendrites of PFC neurons were observed. The distal dendrites of PFC neurons responded most effectively to strong, highly coincident synaptic inputs. Ca²⁺currents near the soma both amplified the effects of these inputs and modulated the spike output pattern. Spike output at the soma was also controlled by the interplay of slowly-inactivating Na⁺ and K⁺ currents. Chapter 6 investigated the modulation of PFC neurons by DA. DA or a D1 but not D2 receptor agonist increased the evoked firing of PFC neurons via a D1- mediated modulation of slowly-inactivating Na⁺ and K⁺ currents. Concurrently, D1 receptor activation reduced burst firing in PFC neurons, due to a attenuation of Ca²⁺ currents. D1 receptor activation also increased both GABA[sub A] IPSPs and NMDA EPSPs. The final chapter of this thesis integrated these data into a cellular model of PFC function and its modulation by DA. It is proposed that DA may tune PFC neurons such that they respond selectively to strong synchronized inputs from other cortical areas. In the presence of DA, working memory processes mediated by the PFC may be influenced selectively by stimuli of behavioral significance.

Despite virtually identical genomes, inbred animals often vary in phenotype, including behaviour, but the molecular basis of this phenomenon is unknown. Our hypothesis is that differences in behaviour between inbred rats are correlated with differential cortical mRNA transcript levels. 40 Lewis rats were subjected to 5 behavioural tests: two were used to categorize 10 animals into either “high” or “low” phenotype groups. Microarray gene expression profiling was performed for 5 rats from each group. Three main analyses were performed to: (1) identify differential expression between the high and low groups, (2) identify correlations between transcript levels and individual behaviour scores, and (3) determine if the results of this replicate experiment overlapped with a previous pilot experiment. Some array results were confirmed by RT-PCR. We found that this experiment did not replicate the findings from the pilot, however several genes of interest were determined and were validated by RT-PCR.

Recent evidence suggests a possible role for the prefrontal cortex (PFC) in sleep/wake regulation and sleep-related electroencephalogram (EEG) activity. This study investigated the effects of cell-specific ibotenic acid lesions to the PFC on sleep-wake patterns and the EEG under baseline conditions and during recovery from a 6 h period of sleep deprivation (SD) using gentle handling in rats. Control rats were injected with saline. PFC lesions had no effects on overall amounts of wake, non rapid-eye movement (NREM) sleep, or rapid-eye movement sleep. However, lesioned animals had fewer wake and NREM sleep episodes and longer mean durations of these episodes particularly during the dark phase. Following SD, no significant lesion effects were observed in sleep rebound or homeostatic increase in NREM EEG delta power (a measure of sleep intensity). These results suggest a role for the PFC in sleep-wake regulation, in particular behavioural state stability.

Despite virtually identical genomes, inbred animals often vary in phenotype, including behaviour, but the molecular basis of this phenomenon is unknown. Our hypothesis is that differences in behaviour between inbred rats are correlated with differential cortical mRNA transcript levels. 40 Lewis rats were subjected to 5 behavioural tests: two were used to categorize 10 animals into either “high” or “low” phenotype groups. Microarray gene expression profiling was performed for 5 rats from each group. Three main analyses were performed to: (1) identify differential expression between the high and low groups, (2) identify correlations between transcript levels and individual behaviour scores, and (3) determine if the results of this replicate experiment overlapped with a previous pilot experiment. Some array results were confirmed by RT-PCR. We found that this experiment did not replicate the findings from the pilot, however several genes of interest were determined and were validated by RT-PCR.

Thesis (M.S. in Computer Science)--Vanderbilt University, May 2005. / Title from title screen. Includes bibliographical references.

Thesis (M.A.)--Miami University, Dept. of Psychology, 2005. / Title from first page of PDF document. Document formatted into pages; contains [1], v, 48 p. : ill. Includes bibliographical references (p. 16-20).

The hippocampal to medial prefrontal cortex (HPC-mPFC) pathway has a role in mnemonic processing. A key function of the hippocampus (HPC) is to organize contextual memories by how they were experienced, and the prefrontal cortex (PFC) retrieves contextual memories by sorting and suppressing irrelevant memories for the task at hand. Studies have highlighted the HPC-mPFC connection in rodents, however, there is a relative paucity of primate studies. The present study addressed this issue by investigating the connection from the HPC to anterior cingulate cortex (ACC; areas 24a, 25 and 32) of the mPFC in rhesus monkeys (Macaca mulatta). The distribution of hippocampal axons and terminals (boutons) was largest in area 25. Bouton diameter was largest in the deep layers of area 25, suggesting an efficient transmission system from the HPC. The robust projections from the HPC terminated most densely in the superficial layers of area 25. The HPC pathway also innervated some inhibitory neurons, labeled for the calcium binding proteins calbindin or calretinin in the superficial layers of the ACC, whereas axons innervated parvalbumin inhibitory neurons in the deep layers of the ACC. The findings suggest that area 25 may be a fundamental pathway from the HPC for memory processing and can be a focal point in therapeutic interventions in neurological and psychiatric diseases.

The activity of neurons in the prefrontal cortex (PFC) may underlie working memory processes in the brain. Both the performance of working memory tasks and the activity of PFC neurons are modulated by dopamine. The goal of the present thesis was to gain insight into the neural basis of working memory by studying the PFC, and the DA system in the PFC, from both a behavioral and cellular perspective. The functional contribution of the PFC to working memory processes in the rat was assessed in Chapter 2 of the present thesis using memory-based foraging tasks on an 8-arm radial maze. The results of these studies indicated that lidocaine-induced inactivations of the PFC selectively disrupted the ability to use mnemonic information to guide foraging, but not the ability to acquire or retain such information. The ability to use mnemonic information to guide foraging was also disrupted by microinjection of a D1 but not D2 receptor antagonist into the PFC. Chapters 3-5 investigated how PFC neurons process synaptic inputs to their dendrites to produce spike output. The intrinsic membrane properties and synaptic responses at the soma and dendrites of deep layer PFC pyramidal neurons were recorded using sharp intracellular or whole-cell patch-clamp techniques in a brain-slice preparation. Different passive and active membrane properties of the soma and dendrites of PFC neurons were observed. The distal dendrites of PFC neurons responded most effectively to strong, highly coincident synaptic inputs. Ca²⁺currents near the soma both amplified the effects of these inputs and modulated the spike output pattern. Spike output at the soma was also controlled by the interplay of slowly-inactivating Na⁺ and K⁺ currents. Chapter 6 investigated the modulation of PFC neurons by DA. DA or a D1 but not D2 receptor agonist increased the evoked firing of PFC neurons via a D1- mediated modulation of slowly-inactivating Na⁺ and K⁺ currents. Concurrently, D1 receptor activation reduced burst firing in PFC neurons, due to a attenuation of Ca²⁺ currents. D1 receptor activation also increased both GABA[sub A] IPSPs and NMDA EPSPs. The final chapter of this thesis integrated these data into a cellular model of PFC function and its modulation by DA. It is proposed that DA may tune PFC neurons such that they respond selectively to strong synchronized inputs from other cortical areas. In the presence of DA, working memory processes mediated by the PFC may be influenced selectively by stimuli of behavioral significance. / Arts, Faculty of / Psychology, Department of / Graduate