Dorsal raphe nucleus (DRN) neurons projects to widespread areas throughout the brain and are involved in many physiological functions and neuropsychiatric disorders. In particular, DRN serotonin (5-HT) neurons are thought to be implicated in major depressive disorder (MDD) as are steroid hormones. Therefore, the aim of this thesis was to assess the effects of some neurosteroids on DRN neurons in non-anaesthetized rats. Initially, we examined electrophysiological properties of dorsal raphe cells across the sleep---wake cycle in non-anaethetized rats. In this first study we characterized six distinct neuronal populations in the DRN based on spike waveform and firing pattern. We then examined the effects of DHEA-S and testosterone (T) on the firing properties of DRN neuronal populations previously characterized. We observed that most populations exhibited an initial decrease in firing activity following one week of treatment. However, there was a great variability in responses across the populations.

Current concepts of hippocampal circuitry assume a large population of excitatory principal neurones whose activity is largely governed by a network of local-circuit GABAergic interneurones. The diversity of hippocampal local-circuit neurones and their synaptic control over principal cell activity was investigated in vitro, in order to define their synaptic connections and functional roles. Single and dual intracellular recordings were made from local-circuit neurones and pyramidal cells in area CA1 of the rat hippocampal slice. Interneurones were tentatively distinguished from pyramidal cells based on their firing as well as their membrane properties. Intracellular labelling of recorded cells with the marker biocytin revealed a diversity of cell types based on differential dendritic and axonal morphology and synaptic connections. The physiological data revealed that all types of interneurone tested evoked inhibitory postsynaptic potentials (IPSPs) in simultaneously recorded pyramidal cells. The IPSPs had fast rise and decay kinetics and the ones tested pharmacologically, were mediated by GABA_A receptors. Similarly, individual interneurones were also shown to innervate other local-circuit interneurones in addition to pyramidal cells, the evoked effects being qualitatively similar in both types of postsynaptic targets. The postsynaptic effect and functional role of one type of hippocampal interneurone, the basket cell, was investigated in greater detail. Basket cell-evoked IPSPs were reliable, but showed some frequency-dependent attenuation. Moreover, basket cell IPSPs were found to interact with intrinsic pyramidal cell conductances to elicit rebound depolarisations and facilitate action potential generation. More detailed investigation showed that basket and axo-axonic cells were particularly effective in entraining pyramidal cell firing and sub-threshold membrane potential oscillations. Through these powerfully tuned mechanisms, sub-types of local-circuit interneurone provide a powerful mechanism to synchronise the activity of pyramidal cells. These results demonstrate a remarkable diversity of GABAergic local-circuit neurones in the hippocampal CA1 area and suggest that specific subtypes of cell mediate different functions.

The present series of experiments was designed to assess the utility of a discrimination procedure for measuring the affective properties of rewarding brain-stimulation. If the rewarding and discriminative stimulus properties of electrical brain stimulation were related, they may share a common substrate and be affected similarly by the same pharmacological manipulations. In Experiment 1, a discrimination procedure was developed to measure the cue properties of EBS delivered to the ventral tegmental area (VTA). Rats with VTA electrodes were trained to obtain food pellets by making a discriminated operant response on one of two levers following pulses of high intensity stimulation, or on the alternate lever after low intensity pulses. Following training, the rats were given tests in which generalized responding to intermediate intensities was measured. These tests were repeated either with conditions kept constant, or with the absolute intensities of the cues delivered within a sesion increased or decreased relative to baseline. The tests with higher or lower intensity ranges were intended to mimic the conditions that might prevail if the perceived intensities of the EBS were modified by drugs. The results of this experiment indicated that generalization gradients remained stable across three tests with conditions kept constant. When higher or lower current ranges were delivered, the discriminated responses were appropriately biased towards one lever or the other, resulting in lateral shifts in the generalization gradients. These results verified that the discrimination procedure provided a stable measure of the EBS stimulus properties, and that this measure was sensitive to changes in the intensities of the cues. In Experiment 2, tests for EBS generalization and self-stimulation (ICSS) were given after injections of vehicle, d-amphetamine (1.0 mg/kg and 2.0 mg/kg) and haloperidol (.075 mg/kg and .10 mg/kg). The results indicated that these doses of amphetamine and haloperidol did not affect the EBS generalization. However, during ICSS sessions, 2.0 mg/kg amphetamine decreased threshold and increased rates for ICSS whereas .10 mg/kg haloperidol resulted in an increase in threshold. These results suggest a dissociation of the stimulus properties of EBS from the DA reward substrate. In Experiment 3, the rats were tested for generalization after injections of physostigmine (.25 mg/kg and .50 mg/kg), scopolamine (.10 mg/kg and .25 mg/kg) and vehicle. Only the high dose of physostigmine (.50 mg/kg) produced significant differences in responding in this experiment. After injection of this drug, lower intensity stimuli elicited responding on the lever appropriate for the high current intensity, indicating a possible augmentation of the stimulus property of a fixed intensity of brain stimulation. The results of this study indicate that the cue properties of VTA brain-stimulation are dissociable from EBS reward related to the activation of DA neurons. However, evidence is provided which suggests that cholinergic neurons may be involved in the mediation of the EBS cues. In as much as cholinergic neurons are also involved in the rewarding effects of VTA brain-stimulation, these results may indicate a relationship between the cue properties of VTA EBS and an acetylcholine reward system. / Arts, Faculty of / Psychology, Department of / Graduate

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published_or_final_version / Anatomy / Master / Master of Medical Sciences

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Anger is commonly referred to in the context of aggressive behaviors. However, little is known about more nuanced effects of this emotion on behavior, nor its neural correlates as a subjective feeling state. For instance, several studies suggest that angry people, in contrast to anxious individuals, perceive risks optimistically. It remains unknown whether these opposing effects of trait anxiety and trait anger on risk perceptions manifest in a direct behavioral measure of risk taking. Our first experiment showed, as predicted, that high trait anxiety was associated with pessimism, whereas anger exerted an optimistic bias on likelihood perceptions. However, these biases did not translate into differences in risk taking behavior. Instead of optimism, impulsivity was highlighted as a mediator of risk proneness in individuals who tend to express anger. A second project investigated the neural basis of anger as an affective state elicited by emotionally evocative social scenes. Participants' attention was directed towards transgressors or their victim, which elicited feelings of anger and sadness respectively. These distinct emotions were associated with differential activity patterns in regions related to affective processing; the amygdala, insula and subgenual anterior cingulate cortex. Individual differences in trait empathy emerged as strong modulators of these activity patterns. In contrast, the ventromedial prefrontal cortex response to transgressors versus victims correlated positively with an individual's tendency to express anger, suggesting a role of this region in the regulation of angry feelings.

The P300 component of the average evoked potential was recorded at Pz during two divided visual field tasks. During a lexical decision task, reaction time and P300 latency were faster to stimuli in the right visual field, indicating that the latency of the P300 may be a useful measure in laterality research. A right visual field advantage was obtained for reaction time in a face perception task and the P300 latency difference showed a similar but non-significant advantage. Use of the P300 latency to assess the validity of the assumptions underlying the application of an additive factors model to divided visual field studies of cerebral assymetry was discussed. The present evidence suggests that the assumptions are valid. / Arts, Faculty of / Psychology, Department of / Graduate

An extensive mapping of the caudate-putamen in the rat for intracranial self-stimulation (ICS) sites »as undertaken to provide additional support for the role of dopamine in brain stimulation reward. Eighty-seven percent of the placements in the neostriatum supported ICS, with self-stimulation rates greater than 250/15 min at 56% of the sites. In a second experiment, animals were prepared with electrodes aimed at the lateral caudate-putamen. Those subjects displaying ICS subsequently received 6-hydroxydopamine lesions to the dopamine cell bodies in the substantia nigra pars compacta either ipsilateral or contralateral to the electrode. The destruction of the dopamine cell bodies attenuated ICS in both groups during the first post-lesion test sessions. However, the rates in the ipsilateral group declined to between 2-9% of control scores, whereas the rates in the contralateral group improved over testing to 72% of control values, 28 days after the lesion. On the basis of these data, it was concluded that unilateral destruction of the dopaminergic nigro-neostriatal (NSB) has two effects on ICS behaviour. First, unilateral reduction of neostriatal dopamine is accompanied by a loss of brain stimulation reward at sites normally innervated by the NSB, specifically the caudate-putamen. Secondly, lesions of the NSB produce a general disruption in bar pressing behaviour, as evidenced by the attenuation of ICS following contralateral lesions. The possible role of the NSB in natural reward is discussed. / Arts, Faculty of / Psychology, Department of / Graduate

Since all chemical and electrical input into the cell / occurs via its plasma membrane, many pharmacological agents and hormones initiate their effects by interacting with receptor sites on the plasma membrane or by passing through the cell membrane and interacting with other membranes within the cell. Generally, the precise mechanisms by which these events occur remain relatively unclear. It was thought for many years that the cell membrane was a relatively static structure which allowed molecules to enter the cell at a rate dependent upon their degree of lipid solubility. However, more recently an increasing body of evidence suggests that cellular membranes are dynamic structures hosting many enzymatic activities and that many drugs or hormones can mediate intracellular effects via these membrane enzyme systems. ... Mammalian brain AChE from the caudate nucleus was chosen as the specific membrane protein to be investigated. Studies were initiated on the rationale that subcellular fractionation and the solubilization of AChE from membrane fractions under various experimental conditions would secure these general goals; (i) to obtain a stable aqueous solution of AChE of high specific activity and yield which would provide the basis of further purification and characterization studies, and (ii) to elucidate some of the basic physicochemical relationships of AChE to membrane components.