Kappa Opioid Receptor in Paraventricular Nucleus of Thalamus - The kappa opioid receptor (KOR) is one of the three opioid receptors. KOR agonists produce analgesic and anti-pruritic effects, but their development for clinical use has been limited by side effects, most importantly dysphoria and psychotomimesis. KOR antagonists display antidepressant- and anti-anxiety-like effects in rodents and may be useful for the treatment of drug addiction in humans. The paraventricular nucleus of the thalamus (PVT), the most dorsal nucleus of the thalamic midline nuclei, is among the brain regions that express high levels of KOR. The PVT receives inputs from the prelimbic, infralimbic and insular cortices, the ventral subiculum and many hypothalamic and brain stem nuclei. The PVT sends dense projections to several limbic structures including the amygdala, the bed nucleus of the stria terminalis, and the core and shell of the nucleus accumbens. The PVT is part of the brain anxiety network and is involved in stress responses, fear, anxiety, arousal, reward, and homeostasis. The KOR level in the PVT is similar to that in the ventral tegmental area, but KOR in the PVT has not yet been characterized. For the proposed studies, we have generated a mutant mouse line expressing tamoxifen-inducible Cre conjugated to KOR (KOR-iCre). In this application, we propose the following three specific aims. For the Aim 1, the origins of afferent projections to PVT KOR- expressing neurons will be determined by Cre-dependent rabies virus-mediated monosynaptic retrograde tracing. The brain regions of efferent projections of PVT KOR-expressing neurons will then be characterized using Cre-dependent anterograde tracing. Whether KOR+ neurons in the PVT projecting to different brain regions receive innervations from different brain areas will also be investigated. Finally, the origin of dynorphin inputs into the PVT will be explored. For the Aim 2, we will elucidate the functions of PVT KOR by examining the effects of conditional deletion of PVT KOR on behaviors such as KOR agonist-induced analgesia in a visceral pain model, conditioned place aversion, naloxone-precipitated withdrawal signs, aversion after chronic morphine and anxiety-like behaviors. For the Aim 3, we will examine the roles of PVT KOR-expressing neurons in stress-related behaviors, fear conditioning and aversion by activation and inhibition of these neurons via chemogenetic approaches. This will be the first time that these PVT KOR-expressing neurons and KOR per se are investigated in a comprehensive manner. Determining the neuronal circuitries in which the KOR is involved and the functional significance of KOR+ circuits will enhance our understanding of KOR functional neuroanatomy and KOR-mediated aversion, anxiety, stress responses and other psychopathology. The knowledge acquired may provide the neuronal basis for developing KOR antagonists as anti-anxiety agents.
