Coordinated forms of noradrenergic plasticity in the locus coeruleus and primary auditory cortex

Abstract

The cerebral cortex is plastic and represents the world according to the significance of sensory stimuli. However, cortical networks are embodied within complex circuits including neuromodulatory systems such as the noradrenergic locus coeruleus, providing information about internal state and behavioral relevance. While norepinephrine is important for cortical plasticity, it is unknown how modulatory neurons themselves respond to changes of sensory input. Here we examine how locus coeruleus neurons are modified by experience, and the consequences of locus coeruleus plasticity on cortical representations and sensory perception. We made whole-cell recordings from rat locus coeruleus and primary auditory cortex (AI), pairing sounds with locus coeruleus activation. Although initially unresponsive, locus coeruleus neurons developed and maintained auditory responses afterwards. Locus coeruleus plasticity induced changes in AI responses lasting at least hours and improved auditory perception for days to weeks. Our results demonstrate that locus coeruleus is highly plastic, leading to substantial changes in regulation of brain state by norepinephrine.

Neuromodulatory influence of norepinephrine during developmental experience-dependent plasticity

“…During the critical period, enhancement of sensory input to the cortex might then occur by a reduction of spontaneous excitatory activity by GABAergic neuron maturation accompanying a broadband boosting of responses to stimuli that activate the adrenergic system. Martins and Froemke (2015) provide support for this idea behaviorally and electrophysiologically by showing that in adult A1, pairing sounds with LC stimulation leads to a transient broadening of frequency tuning followed by a longlasting sharpening at the paired sound frequency. It is likely that NE comodulates such processes along with other neuroNeuro Forum modulators like ACh; however, Shepard et al (2015) indicate that NE exhibits a unique, necessary role in auditory cortex plasticity.…”

“…During cortical plasticity events, NE may shift excitatory/inhibitory balance by exerting a disinhibitory influence on the circuitry. In support of this idea, Martins and Froemke (2015) have shown that in adult primary auditory cortex (A1), disinhibition by LC activation permits BF tuning plasticity. From a developmental standpoint, these effects of NE may function in the background of maturing GABAergic inhibition.…”

“…To affect long-lasting changes in response to sensory experience, sensory signals must overcome two types of inhibition: a tonic inhibition that reduces spontaneous activity in the system and a phasic inhibition that limits the response to a given stimulus. NE is known to act on neuronal circuits to enhance excitatory drive in a broadband fashion by reducing tonic inhibition (Froemke 2015;Martins and Froemke 2015). During the critical period, enhancement of sensory input to the cortex might then occur by a reduction of spontaneous excitatory activity by GABAergic neuron maturation accompanying a broadband boosting of responses to stimuli that activate the adrenergic system.…”

“…This paired stimulation can be accompanied by simultaneous recordings of neuronal responses in A1 to track plasticity. Using paired stimulation and broad antagonism of ␣-adrenergic receptors, Martins and Froemke (2015) implicated these receptors in LC-A1 plasticity. We propose the use of more selective adrenergic antagonists in this paired stimulation protocol to isolate the specific types of ␣-and/or ␤-receptors involved in modulating A1 responses.…”

Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer’s Disease

“…It has been shown that LC is highly plastic and responds to sensory stimulation including auditory stimulation (Snow et al 1999;Martins and Froemke 2015). Indeed, there is coupling between LC and somatosensory-evoked activity (Safaai et al 2015).…”