Characterizing Norepinephrine Release In The Paraventricular Nucleus Of The Hypothalamus
Creators: name: Gerth, Ashlynn I
Publisher: name: University of Illinois at Chicago
Year: 2021
Subjects: Uncategorized

description: Survival hinges on the ability to maintain homeostasis in response to both external and internal threats. The paraventricular nucleus of the hypothalamus (PVN) plays a critical role in orchestrating the various physiological processes needed to address homeostatic challenge. The most well-known function of the PVN is its role in regulating the body’s response to stress; otherwise defined as anything that causes a disruption to physiological equilibrium. The release of corticotrophin-releasing hormone (CRH) – a signaling molecule synthesized and released by cells located in the medial parvocellular (mp) region of the PVN – initiates a complex series of events resulting in an increase of circulating glucocorticoids and ultimately a mobilization of energy stores (Maniscalco &amp; Rinaman, 2017). These succeeding processes make-up what is known as the hypothalamic-pituitary-adrenal (HPA) axis, and is considered the primary hormonal response to stress. Direct projections from central regions monitoring homeostatic need enable the PVN to coordinate appropriate responses to any given physiological threat. Regions of the PVN are densely innervated by catecholaminergic norepinephrine, which has been shown necessary for normal activation of the HPA axis (Rinaman, 2010). Specifically, A2 norepinephrine neurons (located in the caudal medulla) synapse directly onto mpPVN CRH cells via the ventral noradrenergic bundle (VNAB), and provide the major known stimulus of CRH release (Sawchenko &amp; Swanson, 1981). Vagal afferents relaying direct physiological need-state information directly innervate the A2 region, allowing these norepinephrine cells to quickly respond to a variety of stressors. While this circuit has been well documented histologically (Swanson &amp; Kuyper, 1980), little is known about the real-time fluctuations of catecholamine release in the PVN. Neural substrates that are engaged in the body’s response to stress are also reliably activated by acute drug exposure (Armario, 2010). The opponent process theory – a widely cited model of addiction – explains this activation as the physiological response to a drug-induced homeostatic challenge. The addictive nature of abused drugs is driven largely by their supraphysiological effects, such as the amplification of mesolimbic dopamine release thought to be driving the initial reinforcing effects of any given drug. In response to these alterations, opposing mechanisms come online to counteract these imbalances and bring physiological state back to equilibrium. With repeated exposure, the rewarding sensation once felt becomes attenuated, while the compensatory responses become strengthened and produce a negative affect when the drug is absent – thereby increasing the likelihood of relapse (Koob &amp; LeMoal, 2008). While the dopamine system has been extensively examined for its role in drug use, little is known about if and how norepinephrine is affected by drug use. Having a better understanding of how norepinephrine signaling responds to drug exposure will allow for a more comprehensive view of the mechanisms underlying the formation and maintenance of addiction.