Our ability to recall information and events is astounding and dependent on the medial temporal lobe (MTL) memory system. The synaptic interconnections between the neocortex (nCTX), entorhinal cortex (EC), and hippocampus (HPC) are the anatomical basis of this memory system. The electrophysiological basis of memory formation in this system is largely unknown, but the activity patterns that occur during slow wave sleep (SWS) are thought to play an important role. One prominent activity pattern that occurs during SWS is the slow oscillation (SO). It is a large-amplitude rhythm of ~1Hz that was first described in the nCTX and only occurs during SWS and deep anaesthesia. Using the urethane-anaesthetised rat, I provide the first description of the SO in the HPC in Chapter 2. I found that the SO in the HPC was dynamically coordinated with that in the nCTX. Because the EC is the anatomical interface between the nCTX and HPC, I hypothesised that it could be responsible for this coordination. Chapter 3 characterises the SO in the EC and its coordination with both the nCTX and HPC. My results suggested that the synaptic interconnections between the nCTX and HPC via the EC were not solely responsible for SO coordination across these structures. Another possibility is that SO coordination across the nCTX, EC, and HPC occurs via the nucleus reuniens thalami (NReu). In Chapter 4, I delivered trains of electrical stimulation to the frontal cortex (fCTX) to enhance the SO in the nCTX and assess any effect in the HPC. In addition, I delivered the same stimulation trains directly to the medial prefrontal cortex (mpfCTX) and NReu. I found that repeated stimulation in each structure entrained the hippocampal SO. I also found that repeated stimulation of the fCTX and mpfCTX enhanced SO coordination across the nCTX and HPC, but repeated stimulation of the NReu did not. My results suggested that SO coordination across the nCTX and HPC occurs via both the EC and NReu. Understanding the coordination of SO activity across these structures will provide insight to the electrophysiological basis of the MTL memory system and the role of SWS in its function.

The hippocampus appears to carry out spatial memory processing and navigation. As one of the inputs to the hippocampus originates in the perirhinal cortex and the spatial behaviour is affected by lesion of the perirhinal cortex, this structure may be critical for the functioning of hippocampal place cells. To investigate this hypothesis, the firing properties of hippocampal place cells were compared between control rats and rats with perirhinal cortex lesions. Rats were randomly assigned to control and lesion groups. Animals from both groups received recording electrode implantation and the lesion group rats received bilateral perirhinal cortex lesions. In experiment 1, the control and lesioned rats moved freely in an open field. In experiment 2, the control and lesion rats ran for reward in a linear track with either horizontal or vertical grating pattern stimulation along both sidewalls. These two experiments examined the spatial firing and movement-related firing properties of the control and lesion groups; and the theta-related firing properties of the two groups. In addition, experiment 2 investigated the influence of optic flow on these properties between the two groups. In experiment 3, the control and lesion rats were passively moved in the linear track with either a horizontal or vertical grating pattern on both sidewalls. This experiment examined the spatial firing and movement-related firing properties and also investigated the influences of optic flow, motor efferent and proprioceptive information on the firing properties of the control and lesion groups� place cells. The perirhinal cortex lesion affected the spatial firing properties of hippocampal place cells. The place field size in the lesion group was significantly reduced compared to the control group in both open field and linear track experiments. The lesion also altered the movement-related firing properties. The positive relationship between the animal�s movement speed and place cell�s firing rate was disrupted by the perirhinal cortex lesion whether the animals freely ran in the open field or in the linear track. In the open field study, the perirhinal cortex lesion altered the theta-related firing pattern, and the lesion disrupted phase precession in the linear track experiment. Phase precession is that when a rat passes through the place field, the firing of the cell advances progressively and systematically across the phase of the theta cycle from a late to an early phase of the cycle. The lesion also induced poorer theta "quality" of the EEG recorded at the hippocampal fissure. Optic flow affected the spatial firing of hippocampal place cells. The place field size was smaller in both the control and lesion group when the animals received vertical grating pattern stimulation compared to the horizontal grating condition. Change in the levels of optic flow stimulation did not, however, influence the relationship between the animal�s movement speed and place cell�s firing rate in the control group. When the animals were passively moved in a linear track, many of the place cells of both the groups stopped firing. The remaining cells from the control and lesion groups still displayed a place field. The cells in the control group lost the positive relationship between the animal�s movement speed and place cell�s firing rate. The perirhinal cortex lesion affected the spatial, movement- related and theta-related firing properties of hippocampal place cells. Change of optic flow had a subtle effect on the movement-related firing properties of the place cells. The PrhC lesion therefore disrupted motor efferent and proprioceptive input to the HPC rather than visual sensory information. Motor efferent / proprioceptive or vibrissae information may be conveyed from related cortex to the perirhinal cortex. This information may then project from the perirhinal cortex to the hippocampus directly or indirectly via the entorhinal cortex. Future studies could investigate the relationship between whisker stimulation and hippocampal place cell firing properties and further examine the possible role of motor efferent / proprioceptive signals in the firing of these cells.

In the theory of the Behavioral Inhibition System (BIS), Gray and McNaughton (2000) classified events that produce or inhibit goal-directed behaviour into two affective categories: approach versus avoidance. We experience goal-conflict when approximately equal but incompatible approach and avoidance tendencies are concurrently activated. Gray and McNaughton (2000) proposed goal-conflict as a class of mechanisms separable from "simple" mechanisms: Goal-conflict effects are maximal when incompatible approach and avoidance tendencies are balanced, simple effects are maximal when either approach or avoidance tendencies predominate. Gray and McNaughton (2000) saw the hippocampus as a key nexus for resolving goal conflict by recursive amplification of the subjective value of punishment, thereby increasing avoidance tendencies. Rodent hippocampal theta (4-12 Hz) is necessary (but not sufficient) for correct and efficient transmission of hipppocampal outputs. The BIS theory is fundamentally an animal model. It is not clear if a human BIS exists in the same form. Record human hippocampal (4-12 Hz) activity from the scalp is unlikely. However, during goal-conflict resolution, cortically generated theta recorded from the scalp could be modulated by human hippocampal theta. Therefore, superficially recorded 4-12 Hz theta spectra power was used to assess if specific goal-conflict processing activity could be detected in humans. Human goal-conflict processing was assessed in four experiments: the Stop-Signal Task (SST), an existing experimental task, and three variations of a task termed "Choice", created for this thesis. Across experiments, three key conditions were created. Approach and avoidance were balanced in the intermediate condition (maximal goal-conflict). Net approach and avoidance predominated in the adjacent conditions respectively (minimal goal-conflict). Goal-conflict was assessed as the difference between activity in the intermediate condition and the average activity across the adjacent conditions (via extraction of the orthogonal quadratic trend for significance testing). Goal-conflict increased activations consistently at F8, above the right frontal cortex. Increase in task dependent goal-conflict activations were also observed at F7, Fz and F4 above the frontal cortex, and T3, T4, T5 and T6 above the temporal cortex. Activations within the human theta frequency range (4-7 Hz) were consistently detected in the Choice tasks. In the SST, activations spanned the conventional human theta (4-7 Hz) and alpha (8-12 Hz) frequencies. In the Choice tasks, higher conflict theta at T3, T5 and F8 predicted increased avoidance. Taken together, the findings support Gray and McNaugthon�s (2000) views that a) goal-conflict is a class of mechanism separable from simple approach and avoidance; b) goal-conflict processing recruits and increases cortical rhythmic activity within the same frequency range as rodent hippocampal theta (4-12 Hz); and goal-conflict is resolved by increasing the subjective value of punishment, thereby increasing avoidance tendencies. Although speculative, the current work identified a right inferior frontal gyrus neural circuit for slower, and a presupplementary motor area circuit for faster behavioral inhibition during goal-conflict resolution. These circuits are not explicit in the current BIS model.

Anxiety disorder is prevalent and costly. But its diagnosis is underdeveloped and treatment ad hoc. This could be corrected if the neural mechanisms of anxiety were known. All anxiolytic medications produce a decrease in rodent hippocampal theta rhythm - so hippocampal theta could underlie some types of anxiety. But, a review (Chapter 2) showed that ethanol and other anxiolytics increase FM-theta in the human scalp EEG and have other properties unlike hippocampal theta. The experiments in this thesis, therefore, tested for other potential homologues (Chapter 3) of hippocampal theta in the human EEG. The phase of hippocampal theta activity is reset in a working memory task and not an equivalent reference memory task in rats. Furthermore, low doses ethanol increases and high dose ethanol (and other anxiolytics) decrease theta activity. So, EEG was recorded from 15 scalp sites while participants performed non-verbal working memory and reference memory tasks before and after ethanol administration and assessed for the presence of phase-reset and ethanol-related changes in 5-7Hz and 8-11Hz spectral power (chapter 4 and 5). There was little general evidence for stimulus-induced phase-resetting of the ongoing EEG activity (Chapter 6). Increased post-stimulus synchronization in the theta frequency range was accompanied by increases in post-stimulus spectral power - suggesting that the synchronised activity was evoked rather than reset. Across 3 experiments (Chapter 7), low dose ethanol (54.5-146.6[mu]g/l) increased 5-7Hz theta, while the highest dose (307[mu]g/l) reduced task-related-increases in 5-7Hz activity. These effects were noted across electrode locations including frontal-midline sites and particularly at the beginning of the delay period. The suppression of 5-7Hz activity also coincided with an impairment in working memory performance. The dose-response curve for 5-7Hz theta was as predicted from rat hippocampal work. This particular component, linked to high working memory load or task difficulty, is a potential of homologue hippocampal theta. A clear decrease in theta with high dose ethanol, of this type, has not been reported previously. Activity in the 8-11Hz range typically increased with all doses of ethanol. It is clearly not a homologue of hippocampal theta. This is consistent with previous reports of increased alpha with high doses of ethanol - although these have been accompanied by increased, not decreased, theta. There is a potential homologue of hippocampal theta that can be detected in the human EEG (chapter 8); but the observed changes in 5-7Hz activity cannot be localised and may not be related to the hippocampus. It is clear there is more than one type of theta within the human EEG - with opposing sensitivities to ethanol. Critically, these types were detected at a single site and apparently in phase with one another. The current data, together with the previous literature, suggest that theta can be generated concurrently in distinct networks that, under specific task demands, can become coherent and so produce synchonised activity. Future studies need to test higher doses of ethanol and other anxiolytics and use different experimental paradigms to further differentiate the theta systems in the human EEG. Human EEG could be useful for differentiating sub-types of anxiety, and the choice and effectiveness of interventions delivered.

In the theory of the Behavioral Inhibition System (BIS), Gray and McNaughton (2000) classified events that produce or inhibit goal-directed behaviour into two affective categories: approach versus avoidance. We experience goal-conflict when approximately equal but incompatible approach and avoidance tendencies are concurrently activated. Gray and McNaughton (2000) proposed goal-conflict as a class of mechanisms separable from "simple" mechanisms: Goal-conflict effects are maximal when incompatible approach and avoidance tendencies are balanced, simple effects are maximal when either approach or avoidance tendencies predominate. Gray and McNaughton (2000) saw the hippocampus as a key nexus for resolving goal conflict by recursive amplification of the subjective value of punishment, thereby increasing avoidance tendencies. Rodent hippocampal theta (4-12 Hz) is necessary (but not sufficient) for correct and efficient transmission of hipppocampal outputs. The BIS theory is fundamentally an animal model. It is not clear if a human BIS exists in the same form. Record human hippocampal (4-12 Hz) activity from the scalp is unlikely. However, during goal-conflict resolution, cortically generated theta recorded from the scalp could be modulated by human hippocampal theta. Therefore, superficially recorded 4-12 Hz theta spectra power was used to assess if specific goal-conflict processing activity could be detected in humans. Human goal-conflict processing was assessed in four experiments: the Stop-Signal Task (SST), an existing experimental task, and three variations of a task termed "Choice", created for this thesis. Across experiments, three key conditions were created. Approach and avoidance were balanced in the intermediate condition (maximal goal-conflict). Net approach and avoidance predominated in the adjacent conditions respectively (minimal goal-conflict). Goal-conflict was assessed as the difference between activity in the intermediate condition and the average activity across the adjacent conditions (via extraction of the orthogonal quadratic trend for significance testing). Goal-conflict increased activations consistently at F8, above the right frontal cortex. Increase in task dependent goal-conflict activations were also observed at F7, Fz and F4 above the frontal cortex, and T3, T4, T5 and T6 above the temporal cortex. Activations within the human theta frequency range (4-7 Hz) were consistently detected in the Choice tasks. In the SST, activations spanned the conventional human theta (4-7 Hz) and alpha (8-12 Hz) frequencies. In the Choice tasks, higher conflict theta at T3, T5 and F8 predicted increased avoidance. Taken together, the findings support Gray and McNaugthon�s (2000) views that a) goal-conflict is a class of mechanism separable from simple approach and avoidance; b) goal-conflict processing recruits and increases cortical rhythmic activity within the same frequency range as rodent hippocampal theta (4-12 Hz); and goal-conflict is resolved by increasing the subjective value of punishment, thereby increasing avoidance tendencies. Although speculative, the current work identified a right inferior frontal gyrus neural circuit for slower, and a presupplementary motor area circuit for faster behavioral inhibition during goal-conflict resolution. These circuits are not explicit in the current BIS model.

Dissertation (Ph.D.)--University of Toledo, 2007. / "In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Bibliography: p. 70-78, p. 93, p. 132-140, p. 164-168, p. 194-221.

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Tez (Yüksek Lisans) - Süleyman Demirel Üniversitesi, Sağlık Bilimleri Enstitüsü, Biyokimya ve Klinik Biyokimya Anabilim Dalı, 2003. / Bibliyografya var.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.