Probes for ADRB2

In the arcuate nucleus of the hypothalamus (ARH) satiety signaling (anorexigenic) pro-opiomelanocortin (POMC)-expressing and hunger signaling (orexigenic) agouti-related peptide (AgRP)-expressing neurons are key components of the neuronal circuits that control food intake and energy homeostasis. Here, we assessed whether the catecholamine noradrenalin directly modulates the activity of these neurons in mice. Perforated patch clamp recordings showed that noradrenalin changes the activity of these functionally antagonistic neurons in opposite ways, increasing the activity of the orexigenic NPY/AgRP neurons and decreasing the activity of the anorexigenic POMC neurons. Cell type-specific transcriptomics and pharmacological experiments revealed that the opposing effect on these neurons is mediated by the activation of excitatory α1A - and β- adrenergic receptors in NPY/AgRP neurons, while POMC neurons are inhibited via α2A - adrenergic receptors. Thus, the coordinated differential modulation of the key hypothalamic neurons in control of energy homeostasis assigns noradrenalin an important role to promote feeding.

Abstract

BACKGROUND:

Drug memories become labile and reconsolidated after retrieval by presentation of environmental cues (conditioned stimulus, CS) or drugs (unconditioned stimulus, US). Whether CS- and US-retrieval trigger different memory reconsolidation processes is not clear.

METHODS:

Protein synthesis inhibitor or β-AR antagonist was systemically administrated or intra-central amygdala (CeA) infused immediately after cocaine re-exposure in cocaine-conditioned place preference (CPP) or self-administration (SA) mice models. β-ARs were conditional knockout in the CeA to further confirm the role of β-AR in cocaine re-exposure-induced memory reconsolidation of cocaine-CPP.

RESULTS:

Cocaine re-exposure triggered de novo protein synthesis dependent memory reconsolidation of cocaine-CPP. Cocaine-priming-induced reinstatement was also impaired with post cocaine-retrieval manipulation, in contrast to the relapse behavior with post context-retrieval manipulation. Cocaine-retrieval, but not context-retrieval, induced CeA activation. Protein synthesis inhibitor or β1-AR antagonist infused in the CeA after cocaine-retrieval, but not context-retrieval, inhibited memory reconsolidation and reinstatement. β1-AR conditional knockout in the CeA suppressed cocaine-retrieval triggered memory reconsolidation and reinstatement of cocaine-CPP. β1-AR antagonism after cocaine-retrieval also impaired reconsolidation and reinstatement of cocaine-SA.

CONCLUSIONS:

Cocaine reward memory triggered by US-retrieval is distinct from CS-retrieval. US-retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the CeA. Post US-retrieval manipulation can prevent drug memory reconsolidation and relapse to cocaine, thus providing a potential strategy for the prevention of substance addiction.

Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitterreceptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of β2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch.