Activity-dependent constraints on catecholamine signaling

Abstract

Catecholamine signaling is thought to modulate cognition in an inverted-U relationship, but the mechanisms are unclear. We measured norepinephrine and dopamine release, postsynaptic calcium responses, and interactions between tonic and phasic firing modes under various stimuli and conditions. High tonic activity in vivo depleted catecholamine stores, desensitized postsynaptic responses, and decreased phasic transmission. Together this provides a clearer understanding of the inverted-U relationship, offering insights into psychiatric disorders and neurodegenerative diseases with impaired catecholamine signaling.

Shining light on the noradrenergic system

“…As other brain areas, such as nuclei A1, A2, A5, A7, and subcoeruleus, also express NA, 107 – 111 we see great opportunity for discovery by applying similar methods to these subdivisions of the central NA system. On the other hand, with the expansion of the color palette of genetically encoded biosensors, such as non-green GECIs, 112 , 113 red-shifted dopamine and NA sensors, 96 , 114 , 115 and far-red genetically encoded voltage indicators, 116 we expect a multiplication of studies that multiplex neurophotonics methods to measure NA release in conjunction with other brain signals 98 , 101 . Furthermore, the use of genetically encoded fluorescent sensors for NA eliminates the need for transgenic approaches, thus measurements of fast NA dynamics can be performed in any animal models.…”

“…On the other hand, with the expansion of the color palette of genetically encoded biosensors, such as non-green GECIs, 112 , 113 red-shifted dopamine and NA sensors, 96 , 114 , 115 and far-red genetically encoded voltage indicators, 116 we expect a multiplication of studies that multiplex neurophotonics methods to measure NA release in conjunction with other brain signals. 98 , 101 Furthermore, the use of genetically encoded fluorescent sensors for NA eliminates the need for transgenic approaches, thus measurements of fast NA dynamics can be performed in any animal models. In summary, neurophotonics methods, in combination with genetically encoded biosensors, have become indispensable for studying the LC-NA system’s function during behavior.…”

“…By imaging NA sensors in combination with optogenetics, researchers have begun to reveal the link between LC neuronal activity and NA release in target regions 22 , 93 , 94 , 96 , 101 . When combining these tools, it is critical to select optically compatible molecules, to avoid any interference between the excitation wavelengths of the opsin and the sensor.…”

“…When combining these tools, it is critical to select optically compatible molecules, to avoid any interference between the excitation wavelengths of the opsin and the sensor. For example, by infecting LC-NA neurons with a red-shifted opsin and expressing GRABNE in the thalamus and the basal forebrain, researchers have demonstrated the interaction between the tonic and phasic modes of LC firing and NA release during acute stress exposure 101 . Multiplexing these biosensors with other optical tools will potentially be transformative for our understanding of the NA system.…”

“…By imaging NA sensors in combination with optogenetics, researchers have begun to reveal the link between LC neuronal activity and NA release in target regions. 22 , 93 , 94 , 96 , 101 When combining these tools, it is critical to select optically compatible molecules, to avoid any interference between the excitation wavelengths of the opsin and the sensor. For example, by infecting LC-NA neurons with a red-shifted opsin and expressing in the thalamus and the basal forebrain, researchers have demonstrated the interaction between the tonic and phasic modes of LC firing and NA release during acute stress exposure.…”