Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions

Abstract

Central noradrenergic (NA) signaling is broadly implicated in behavioral and physiological processes related to attention, arousal, motivation, learning and memory, and homeostasis. This review focuses on the A2 cell group of NA neurons, located within the hindbrain dorsal vagal complex (DVC). The intra-DVC location of A2 neurons supports their role in vagal sensory-motor reflex arcs and visceral motor outflow. A2 neurons also are reciprocally connected with multiple brain stem, hypothalamic, and limbic forebrain regions. The extra-DVC connections of A2 neurons provide a route through which emotional and cognitive events can modulate visceral motor outflow and also a route through which interoceptive feedback from the body can impact hypothalamic functions as well as emotional and cognitive processing. This review considers some of the hallmark anatomical and chemical features of A2 neurons, followed by presentation of evidence supporting a role for A2 neurons in modulating food intake, affective behavior, behavioral and physiological stress responses, emotional learning, and drug dependence. Increased knowledge about the organization and function of the A2 cell group and the neural circuits in which A2 neurons participate should contribute to a better understanding of how the brain orchestrates adaptive responses to the various threats and opportunities of life and should further reveal the central underpinnings of stress-related physiological and emotional dysregulation.

Fig. 1.

Immunoperoxidase localization of dopamine-β-hydroxylase (DbH; left) and phenylethanolamine N-methyltransferase (PNMT; right ) within the caudal dorsomedial medulla of an adult male Sprague-Dawley rat. Side-by-side panels represent closely adjacent tissue sections. Top 4: caudal levels of the A2 cell group (∼14.6 mm caudal to bregma). Bottom 4: most rostral levels (∼13.3 mm caudal to bregma). DbH-positive neurons within the A2 cell group are indicated by arrows. AP, area postrema; cc, central canal; DMV, dorsal motor nucleus of the vagus; NST, nucleus of the solitary tract; 4, fourth ventricle.

Fig. 2.

Dual immunofluorescence labeling for DbH (red) and PNMT (green) in a tissue section through the rat dorsomedial medulla (∼13.3 mm caudal to bregma) where neurons of the A2 and C2 cell groups intermingle. 4, fourth ventricle.

Fig. 3.

Dual immunofluorescence labeling of anterogradely-transported Phaseolus vulgaris leucoagglutinin (PhAL) neural tracer (green) and DbH (red) identifying axons in the medial parvocellular (mp) and lateral magnocellular (lm) subregions of the paraventricular nucleus of the hypothalamus (PVN). PhAL was microinjected iontophoretically into a portion of the A2 region in an adult male Sprague-Dawley rat 14 days before death (see Ref. 201).

Fig. 4.

Dual immunoperoxidase labeling of cFos protein (blue/black nuclear label) and cytoplasmic DbH (brown label) within the caudal visceral NST. This section was taken from a rat perfused with fixative 60 min after intraperitoneal administration of cholecystokinin octapeptide (100 μg/kg body wt) to stimulate vagal sensory inputs to the NST. Arrows point out activated (i.e., cFos-positive) A2 neurons (see Refs. and 213).