Prefrontal cortex (PFC) is critical to behavioral flexibility and, hence, the top-down control over bottom-up sensory information. The mechanisms underlying this capacity have been hypothesized to involve the propagation of alpha/beta (8-30 Hz) oscillations via feedback connections to sensory regions. In contrast, gamma (30-160 Hz) oscillations are thought to arise as a function of bottom-up, feedforward stimulation. To test the hypothesis that such oscillatory phenomena embody such functional roles, we assessed the performance of nine monkeys on tasks of learning, categorization, and working memory concurrent with recording of local field potentials (LFPs) from PFC. The first set of tasks consisted of two classes of learning: one, explicit and, another, implicit. Explicit learning is a conscious process that demands top-down control, and in these tasks alpha/beta oscillations tracked learning. In contrast, implicit learning is an unconscious process that is automatic (i.e. bottom up), and in this task alpha/beta oscillations did not track learning. We next looked at dot-pattern categorization. In this task, category exemplars were generated by jittering the dot locations of a prototype. By chance, some of these exemplars were similar to the prototype (low distortion), and others were not (high distortion). Behaviorally, the monkeys performed well on both distortion levels. However, alpha/beta band oscillations carried more category information at high distortions, while gamma-band category information was greatest on low distortions. Overall, the greater the need for top-down control (i.e. high distortion), the greater the beta, and the lesser the need (i.e. low distortion), the greater the gamma. Finally, laminar electrodes were used to record from animals trained on working memory tasks. Each laminar probe was lowered so that its set of contacts sampled all cortical layers. During these tasks, gamma oscillations peaked in superficial layers, while alpha/beta peaked in deep layers. Moreover, these deep-layer alpha/beta oscillations entrained superficial alpha/beta, and modulated the amplitude of superficial-layer gamma oscillations. These laminar distinctions are consistent with anatomy: feedback neurons originate in deep layers and feedforward neurons in superficial layers. In summary, alpha/beta oscillations reflect top-down control and feedback connectivity, while gamma oscillations reflect bottom-up processes and feedforward connectivity.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 131-154).

Most of the extant humor research has focused on humor comprehension with only a few studies investigating humor appreciation as a separate construct. The purpose of this investigation was to determine the relation between humor and underlying cognitive processes. Literature on brain injured individuals has indicated that working memory, verbal and visual-spatial reasoning, cognitive flexibility, and concept formation are related to performance on comprehension tests of humor. In this study, cognitive processes underlying both verbal and nonverbal humor were investigated in a sample of healthy young adults. There is evidence that semantic and phonological humor are associated with different neural networks; therefore, both semantic and phonological humor were explored. Studies investigating physiological arousal and humor have indicated that arousal is necessary for the experience of humor. This suggests that the appreciation of humor may require the integration of cognitive and affective information, a process mediated by the ventromedial prefrontal cortex (VMPFC). Thus, a second goal of this study was to investigate the relationship between humor comprehension and appreciation and the VMPFC, by including experimental tasks that previously have been linked to VMPFC functioning. Participants included 94 undergraduate psychology students between the ages of 18 and 39 years. Participants watched film clips and listened to jokes. After the presentation of each joke and each film clip, they completed a humor comprehension/appreciation inventory developed for this study. They also completed measures assessing a range of cognitive abilities hypothesized to underlie humor perception. Hierarchical regression analyses revealed that verbal reasoning was predictive of semantic humor comprehension, indicating that verbal reasoning is a core cognitive ability for the comprehension of jokes in which the humor depends on factors other than simple word play. Cognitive measures were not predictive of phonological humor comprehension or nonverbal humor comprehension. Hierarchical regression analyses revealed that the indicators of VMPFC functioning did not correlate with either humor comprehension or humor appreciation and did not moderate the relation between humor comprehension and humor appreciation. Future research is necessary to elucidate the relationships between cognitive abilities and humor perception and to further explore the contribution of the VMPFC to humor appreciation.

The present study was conducted to determine the effect of differential endogenous estrogen exposure in rats on stress-induced changes in spatial working memory. Subjects comprised male (n=8) and female (n=10) Sprague-Dawley rats, which were trained to complete a T maze, delayed alternation task. Performance was scored as a percentage of trials during which the correct maze arm was selected. Subjects scores were recorded after 1 and 2 hours of restraint stress, as well as after 1 hour of unimpeded movement in a cage placed in the testing room. Restraint stress was effected through physical confinement within plastic, cylindrical tubing. Female subjects underwent each of the testing conditions twice, during periods of high and low endogenous estrogen exposure, as ascertained by microscopic examination of vaginal epithelial cells for estrous cycle stage determination. Females in proestrus (elevated endogenous estrogen exposure) subjected to 1 hour of restraint performed significantly worse than their baseline scores (p=0.0017) or females in estrus (low endogenous estrogen exposure) after 1 hour of restraint (p=0.00014). After 1 hour of restraint, females in proestrus also committed an increased rate of perseverative errors compared to females in estrus, although this increase did not achieve statistical significance (p=0.06). No appreciable differences existed among subject groups in baseline performance or subsequent to 2 hours of restraint stress. Resultant data indicate impaired working memory among female rats under conditions of stress in the context of elevated endogenous estrogen exposure. This study, then, suggests a potential synergistic effect of stress and estrogen in compromising prefrontal cortex function and, therefore, may lend insight into the observed sex-related disparity in the incidence of major depressive disorder and other anxiety-related mood disorders.

Dopamine signaling in the prefrontal cortex is thought to play a role in ethanol abuse. However, little is known about how ethanol affects dopamine signaling in the region. There are a few rodent studies regarding the matter, but both the pharmacological effects of ethanol and the effects of self-administered ethanol on extracellular dopamine in the medial prefrontal cortex remain unclear. The goal of the studies conducted for this dissertation is to clarify these relationships. To accomplish this, we monitored both dialysate dopamine and ethanol concentrations in the medial prefrontal cortex of Long Evans rats while an experimenter administered or a rat operantly self-administered ethanol. In naïve rats, dopamine dose-dependently increased after the intravenous infusions of a 10% ethanol solution, while no changes were noted after saline infusions. In rats trained to orally self-administer drinking solutions, dopamine transiently increased at the initiation of consumption in both ethanol-plus-sucrose- and sucrose-solution-consuming rats. Dopamine concentrations remained significantly elevated for the entire 21-minute drinking period in the ethanol-plus-sucrose-consuming group and for the first seven minutes of the drink period in the sucrose-consuming group. Additionally, in the ethanol-plus-sucrose-consuming group, dialysate ethanol concentrations were lowest at the initiation of drinking and then slowly increased, peaking 35 minutes after drinking commenced. Taken together, these data suggest that the mesocortical dopamine system is responsive to acute, intravenous and repeatedly, orally, self-administered ethanol. It appears that direct pharmacological effects of ethanol were responsible for the dopamine increase after acute, ethanol administration. Furthermore, while is it possible that the direct pharmacological effects of ethanol also bolstered the dopamine response seen after ethanol self-administration, we cannot firmly conclude by what mechanism ethanol elicited the differences. Overall, our clarifying and novel results support a role for the mesocortical dopamine system in ethanol abuse, which deserves continued investigation. In addition to completing the two aforementioned data studies, we also published the methods we use to monitor dialysate ethanol concentrations, in a specific brain region, during ethanol self-administration in a video-methods journal. The methods are presented in both a detailed written protocol, as well as a video demonstrating how to perform the procedures. / text

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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.