Norepinephrine links astrocytic activity to regulation of cortical state

Abstract

Cortical state, defined by population-level neuronal activity patterns, determines sensory perception. While arousal-associated neuromodulators—including norepinephrine (NE)—reduce cortical synchrony, how the cortex resynchronizes remains unknown. Furthermore, general mechanisms regulating cortical synchrony in the wake state are poorly understood. Using in vivo imaging and electrophysiology in mouse visual cortex, we describe a critical role for cortical astrocytes in circuit resynchronization. We characterize astrocytes’ calcium responses to changes in behavioral arousal and NE, and show that astrocytes signal when arousal-driven neuronal activity is reduced and bi-hemispheric cortical synchrony is increased. Using in vivo pharmacology, we uncover a paradoxical, synchronizing response to Adra1a receptor stimulation. We reconcile these results by demonstrating that astrocyte-specific deletion of Adra1a enhances arousal-driven neuronal activity, while impairing arousal-related cortical synchrony. Our findings demonstrate that astrocytic NE signaling acts as a distinct neuromodulatory pathway, regulating cortical state and linking arousal-associated desynchrony to cortical circuit resynchronization.

The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex

“…This observation correlates well with our observation of a decreased duration of NA effect on IPSC frequency during NA wash out in Adra1a-shRNA mice (Figure 4E). Based on their data, Reitman and colleagues propose that α1A-NAR signaling in astrocytes is important to regulate the magnitude and shape of neuronal responses to NA, probably through the specific modulation of interneuron activity (Reitman et al, 2023), a conclusion consistent with our findings. Indeed, it is not only brain state transitions but also synaptic plasticity that is dependent on the activity of GABAergic interneurons (Calcagnotto, 2016;Tremblay et al, 2016;Zucca et al, 2017;McCormick et al, 2020).…”

“…Kohro and colleagues found that astroglial α1A-NAR is necessary for noradrenergic modulation of mechanical pain in spinal cord (Kohro et al, 2020), while the Paukert lab confirmed a central role of α1A-NAR in generating [Ca 2+ ] transients in (cerebellar) astrocytes (Ye et al, 2020;Salinas-Birt et al, 2023). Crucially, Reitman and colleagues demonstrated that α1A-NAR-mediated astrocyte responses act as an important negative feedback mechanism, limiting the effects of NA on cortical circuit activity (Reitman et al, 2023). Indeed, while increased arousal, and the associated phasic NA release, initially desynchronizes cortical networks, consistent with the known effects of NA (Polack et al, 2013;McGinley et al, 2015), the authors observed that α1A-NAR signaling in astrocytes was important to counteract effects of arousal on neuronal activity, restoring circuits to a more synchronized state, notably after the effects of phasic NA release on neuronal activity peaked (Reitman et al, 2023).…”

“…Based on this anatomical evidence, NA has been proposed to signal principally through volume transmission, with astrocytes as major targets (Hirase et al, 2014;Wahis and Holt, 2021). Cortical astrocyte [Ca 2+ ] responses to phasic NA release have been reported, with one adrenoreceptor (NAR) appearing central to these responses -α1-NAR (Bekar et al, 2008;Ding et al, 2013;Paukert et al, 2014;Slezak et al, 2019;Oe et al, 2020;Reitman et al, 2023). To date, however, it is not clear whether this is a direct effect of NA on astrocytes, an indirect effect resulting from NA acting on neurons or a combination of both.…”

“…Crucially, Reitman and colleagues demonstrated that α1A-NAR-mediated astrocyte responses act as an important negative feedback mechanism, limiting the effects of NA on cortical circuit activity (Reitman et al, 2023). Indeed, while increased arousal, and the associated phasic NA release, initially desynchronizes cortical networks, consistent with the known effects of NA (Polack et al, 2013;McGinley et al, 2015), the authors observed that α1A-NAR signaling in astrocytes was important to counteract effects of arousal on neuronal activity, restoring circuits to a more synchronized state, notably after the effects of phasic NA release on neuronal activity peaked (Reitman et al, 2023). With this study, we sought to test whether α1A-NAR signaling is important to generate [Ca 2+ ] transients in cortical astrocytes and aimed to better understand how it modulates neuronal network activity on different timescales.…”

“…With this study, we sought to test whether α1A-NAR signaling is important to generate [Ca 2+ ] transients in cortical astrocytes and aimed to better understand how it modulates neuronal network activity on different timescales. Previous studies looking at the role of NA in cortex reported transient increases in astrocyte [Ca 2+ ] in supragranular layers (layers I-III) (Bekar et al, 2008;Ding et al, 2013;Paukert et al, 2014;Slezak et al, 2019;Oe et al, 2020;Reitman et al, 2023), consistent with the pattern of Adra1a expression observed by Reitman and colleagues (Reitman et al, 2023). Therefore, we chose to focus on the same layers in mouse primary visual cortex (V1), as astrocytes in this brain region have been shown to exert powerful effects on the plasticity of neuronal circuits involved in visual information processing (Müller and Best, 1989;Chen et al, 2012;Pankratov and Lalo, 2015;Monai et al, 2016;Hennes et al, 2020;Ribot et al, 2021).…”