Compounds that interact with Group II metabotropic glutamate receptors (mGluRs) have antipsychotic effects in animal models. These drugs have also shown efficacy in the treatment of schizophrenia in humans. The mechanism of action is believed to arise from a reduction of glutamatergic transmission in limbic and forebrain regions commonly associated with this disorder. Previous anatomical tracer and lesion studies have revealed that neurons of the paraventricular nucleus of the thalamus (PVT) are an important source of the glutamatergic drive to these specific regions. However, the function of Group II mGluRs in the PVT remains to be determined. Whole-cell recordings from PVT neurons reveal that activation of these receptors has two interesting effects; it reduces calcium entry through voltage-gated calcium channels and it causes neurons to hyperpolarize. These two effects may contribute to affect the excitability of PVT neurons, an action that may underlie the effectiveness of Group II mGluR-activating compounds.

Compounds that interact with Group II metabotropic glutamate receptors (mGluRs) have antipsychotic effects in animal models. These drugs have also shown efficacy in the treatment of schizophrenia in humans. The mechanism of action is believed to arise from a reduction of glutamatergic transmission in limbic and forebrain regions commonly associated with this disorder. Previous anatomical tracer and lesion studies have revealed that neurons of the paraventricular nucleus of the thalamus (PVT) are an important source of the glutamatergic drive to these specific regions. However, the function of Group II mGluRs in the PVT remains to be determined. Whole-cell recordings from PVT neurons reveal that activation of these receptors has two interesting effects; it reduces calcium entry through voltage-gated calcium channels and it causes neurons to hyperpolarize. These two effects may contribute to affect the excitability of PVT neurons, an action that may underlie the effectiveness of Group II mGluR-activating compounds.

Compounds that interact with Group II metabotropic glutamate receptors (mGluRs) have antipsychotic effects in animal models. These drugs have also shown efficacy in the treatment of schizophrenia in humans. The mechanism of action is believed to arise from a reduction of glutamatergic transmission in limbic and forebrain regions commonly associated with this disorder. Previous anatomical tracer and lesion studies have revealed that neurons of the paraventricular nucleus of the thalamus (PVT) are an important source of the glutamatergic drive to these specific regions. However, the function of Group II mGluRs in the PVT remains to be determined. Whole-cell recordings from PVT neurons reveal that activation of these receptors has two interesting effects; it reduces calcium entry through voltage-gated calcium channels and it causes neurons to hyperpolarize. These two effects may contribute to affect the excitability of PVT neurons, an action that may underlie the effectiveness of Group II mGluR-activating compounds.

Compounds that interact with Group II metabotropic glutamate receptors (mGluRs) have antipsychotic effects in animal models. These drugs have also shown efficacy in the treatment of schizophrenia in humans. The mechanism of action is believed to arise from a reduction of glutamatergic transmission in limbic and forebrain regions commonly associated with this disorder. Previous anatomical tracer and lesion studies have revealed that neurons of the paraventricular nucleus of the thalamus (PVT) are an important source of the glutamatergic drive to these specific regions. However, the function of Group II mGluRs in the PVT remains to be determined. Whole-cell recordings from PVT neurons reveal that activation of these receptors has two interesting effects; it reduces calcium entry through voltage-gated calcium channels and it causes neurons to hyperpolarize. These two effects may contribute to affect the excitability of PVT neurons, an action that may underlie the effectiveness of Group II mGluR-activating compounds.

Hydrogen sulfide (H2S) is a novel neurotransmitter that has been shown to influence cardiovascular function as well as other autonomic and endocrine functions by targeting a wide range of ion channels. Using whole-cell electrophysiology, I have investigated the potential role of H2S in the regulation of neuronal excitability in the paraventricular nucleus of the hypothalamus (PVN), which is a central relay centre for autonomic and endocrine function. In current-clamp recordings, sodium hydrosulfide hydrate (NaHS), when perfused onto PVN slices at various concentrations (0.1, 1, 10, and 50 mM), elicited a concentration-dependent response relationship from the majority of recorded neurons, with almost exclusively depolarizing effects. Input resistance differences from baseline, and during the NaHS-induced depolarization, uncovered a biphasic response, implicating both a potassium (K+) and non-selective cation conductance. In order to further investigate H2Ss effects on K+ conductances, we used both voltage- and current-clamp techniques to examine the effects of NaHS at either 1 or 10 mM on both the transient and sustained voltage-activated K+ currents in these neurons. We applied TEA+ (10 mM) to isolate the transient/rapidly inactivating current (IA) and 4-AP (5 mM) to isolate the sustained/delayed rectifier current (IK), and were able to show that both of these conductances were significantly reduced by H2S. Finally, we were able to demonstrate, using current-clamp, that when 4-AP and TEA+ were applied together with NaHS, they were able to completely eliminate the previously observed NaHS-induced depolarization, and the effects on membrane potential reversed to show a small hyperpolarization. These data highlight the potential role of H2S as a critical modulator of the voltage-gated repolarizing conductances, IA and IK, which in turn regulate neuronal excitability within the PVN. This can have a large impact on the way neurotransmitters and hormones such as vasopressin, oxytocin, corticotrophin-releasing hormone, and thyrotrophin-releasing hormone are released from the PVN, which influence a wide range of neuroendocrine and autonomic functions such as cardiovascular function, fluid balance, and food intake. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2013-09-13 10:51:34.585

The hormone relaxin regulates the release of the magnocellular hormones, oxytocin and vasopressin, from the central nervous system. Studies have yet to determine whether relaxin regulates magnocellular hormone release through the circumventricular organs alone, or whether relaxin can act on the brain regions containing the magnocellular neurons as well. The paraventricular nucleus of the hypothalamus was isolated from other brain regions and maintained in vitro, in order evaluate the effects of the relaxin and relaxin-3 on the somatodendritic release of oxytocin and vasopressin. At 50 nM concentrations, relaxin induced oxytocin release, while relaxin-3 inhibited oxytocin release. Neither relaxin nor relaxin-3 had an effect on the vasopressin release, however the RXFP3 specific agonist, R3/I5, induced vasopressin release. The effect of the relaxin peptides on the electrical activity of neurons in the paraventricular nucleus was also evaluated. Relaxin depolarized magnocellular neurons while relaxin-3 hyperpolarized the neurons. Relaxin and relaxin-3 appear to have differential effects on the magnocellular neurons of the paraventricular nucleus.

Hypertension (HTN) is a critical public health issue estimated to contribute to 10% of deaths worldwide. Additionally, the salt sensitivity of blood pressure, an exaggerated pressor response to elevated dietary sodium intake, is estimated to be present in approximately 50% of the hypertensive population and 25% of the normotensive population. This is a critical problem as the average American consumes roughly three times the daily sodium intake recommended by the American Heart Association. Our laboratory has previously identified a critical role of Hypothalamic Paraventricular Nucleus (PVN) Gαi2 proteins in the maintenance of salt resistance and normotension in the rat. Salt resistant rats such as the Sprague-Dawley (SD) rat site- specifically upregulate these proteins in response to elevated dietary sodium intake to facilitate sympathoinhibition, natriuresis, and normotension. In contrast, in the Dahl Salt Sensitive (DSS) rat, and in salt resistant rats in which this protein is experimentally downregulated, our laboratory has identified the development of renal nerve-dependent sympathoexcitation and salt-sensitive hypertension (ssHTN). However, the neural mechanisms whereby PVN Gαi2 proteins facilitate salt resistance are unclear. In addition, there is a robust literature in other rat models of HTN suggesting that both neuroinflammation in the PVN as well as an imbalance between PVN inhibitory GABAergic and excitatory glutamatergic signaling contribute to elevations in sympathetic outflow to promote HTN. In this study, SD rats infused chronically with either targeted Gαi2 oligodeoxynucleotides (ODNs) or control scrambled (SCR) ODNs and challenged with either normal (0.6% NaCl) or high-salt (4% NaCl) diets were used to demonstrate that 1) PVN microglial activation and associated pro-inflammatory cytokine production contribute to the development of Gαi2 protein dependent ssHTN, 2) sex-dependent PVN microglial-mediated neuroinflammation precedes and likely drives the development of sympathoexcitation following high dietary sodium administration in male but not female Gαi2 protein dependent ssHTN, and 3) PVN GABAergic and glutamatergic signaling is disrupted and imbalanced, favoring excitation over inhibition, following elevated dietary sodium intake in Gαi2 protein dependent ssHTN. Together, these findings shed light on the pathological neural processes that occur in the absence of PVN Gαi2 protein upregulation and reveal potential mechanistic targets in the management of ssHTN.

The naked mole-rat (Heterocephalus glaber) demonstrates a strict social and reproductive hierarchy. Oxytocin (OXT) is a peptide hormone that acts both peripherally and centrally in the regulation of a number of sexual and social behaviours. The main area of central production of this peptide is the paraventricular nucleus of the hypothalamus (PVN). The present study characterized differences that exist in OXT neurons in this region. Breeders and subordinates from established colonies were sacrificed and brains were processed for OXT-immunoreactivity. Four further groups of paired animals underwent various social and hormonal manipulations (opposite-sex paired, same sex-paired, opposite-sex/gonadectomised paired, opposite-sex/vasectomized paired) and were also used for analysis. Results showed that subordinate naked mole-rats had significantly more OXT-immunoreactive neurons in the PVN than either breeders or paired animals that had been gonadectomised. However, no differences were found on measures of OXT cell volume. Possible functional significance of these differences is discussed.

The naked mole-rat (Heterocephalus glaber) demonstrates a strict social and reproductive hierarchy. Oxytocin (OXT) is a peptide hormone that acts both peripherally and centrally in the regulation of a number of sexual and social behaviours. The main area of central production of this peptide is the paraventricular nucleus of the hypothalamus (PVN). The present study characterized differences that exist in OXT neurons in this region. Breeders and subordinates from established colonies were sacrificed and brains were processed for OXT-immunoreactivity. Four further groups of paired animals underwent various social and hormonal manipulations (opposite-sex paired, same sex-paired, opposite-sex/gonadectomised paired, opposite-sex/vasectomized paired) and were also used for analysis. Results showed that subordinate naked mole-rats had significantly more OXT-immunoreactive neurons in the PVN than either breeders or paired animals that had been gonadectomised. However, no differences were found on measures of OXT cell volume. Possible functional significance of these differences is discussed.

published_or_final_version / Physiology / Master / Master of Philosophy