From hypothalamic peptides to the regulation of dopamine in the nucleus accumbens: the introduction of the paraventricular nucleus of the thalamus in a novel hypothalamic-thalamic-striatal circuit

Parsons, Matthew P. (2006) From hypothalamic peptides to the regulation of dopamine in the nucleus accumbens: the introduction of the paraventricular nucleus of the thalamus in a novel hypothalamic-thalamic-striatal circuit. Masters thesis, Memorial University of Newfoundland.

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Abstract

Previous studies have demonstrated that the para ventricular nucleus of the thalamus (PVT) receives heavy projections from numerous hypothalamic peptides involved in energy homeostasis and brainstem monoamines involved in various aspects of stress and arousal. Not surprisingly, the PVT is highly active during periods of active waking as well as stress and lesions of the PVT influence feeding behavior and anticipatory reactions to cues signaling food reward. Furthermore, the PVT sends a dense glutamatergic projection to the same regions of the nucleus accumbens shell (NacSh) receiving heavy dopaminergic innervation from the ventral tegmental area. Although numerous cortical afferents to the accumbens have been shown to mediate a glutamate-dependent regulation of dopamine efflux within the NacSh, little is known regarding the role of PVT terminals within this region of the ventral striatum. Initial anatomical experiments were done to examine the innervation of the PVT and adjacent thalamic nuclei by two recently discovered hypothalamic peptides termed the orexins and cocaine and amphetamine related transcript (CART), both of which have been heavily implicated in stress and arousal as well as energy homeostasis. Specifically, orexin and CART peptides fibers were investigated in terms of their relationship and proximity to PVT neurons projecting to the NacSh. Further experiments were done using in vivo voltammetry to examine the effects of electrical stimulation of the PVT on dopamine efflux in the NacSh. The PVT was found to receive heavy projections from both orexin immunopositive and CART immunopositive fibers whereas adjacent thalamic nuclei received considerably less or no innervation whatsoever from either peptide. Orexin and CART fibers in the PVT were found to co-express immunoreactivity for synaptophysin, a marker for presynaptic exocytotic release, suggesting that these neuropeptides are actively released within the PVT. High magnification confocal and light microscopy revealed frequent appositions between orexin and CART fiber varicosities and PVT neurons projecting to the NacSh. Voltammetric recordings from the NacSh demonstrated that brief electrical stimulation of the PVT (400 µA, 40Hz, 1.0 ms for 5s) resulted in a transient increase in dopamine oxidation current within the NacSh. The PVT –evoked response was found to be insensitive to inhibition of midbrain dopamine neurons, suggesting a presynaptic regulation of dopamine release. Indeed, an immediate attenuation of PVT evoked dopamine transients was observed upon intra-accumbens infusion of the ionotropic glutamate receptor antagonist kynurenic acid. It is hypothesized that this hypothalamic-thalamic-striatal circuit is important in the facilitation of specific motivated behaviors and is discussed in terms of both a stress and arousal induced increase in dopamine efflux as well as a dopaminergic modulation of food-seeking behavior.

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