Locus Coeruleus Stimulation Recruits a Broad Cortical Neuronal Network and Increases Cortical Perfusion

The locus coeruleus (LC), the main source of brain noradrenalin (NA), modulates cortical activity, cerebral blood flow (CBF), glucose metabolism, and blood–brain barrier permeability. However, the role of the LC–NA system in the regulation of cortical CBF has remained elusive. This rat study shows that similar proportions (∼20%) of cortical pyramidal cells and GABA interneurons are contacted by LC–NA afferents on their cell soma or proximal dendrites. LC stimulation induced ipsilateral activation (c-Fos upregulation) of pyramidal cells and of a larger proportion (>36%) of interneurons that colocalize parvalbumin, somatostatin, or nitric oxide synthase compared with pyramidal cells expressing cyclooxygenase-2 (22%, p < 0.05) or vasoactive intestinal polypeptide-containing interneurons (16%, p < 0.01). Concurrently, LC stimulation elicited larger ipsilateral compared with contralateral increases in cortical CBF (52 vs 31%, p < 0.01). These CBF responses were almost abolished (−70%, p < 0.001) by cortical NA denervation with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] and were significantly reduced by α- and β-adrenoceptor antagonists (−40%, p < 0.001 and −30%, p < 0.05, respectively). Blockade of glutamatergic or GABAergic neurotransmission with NMDA or GABAA receptor antagonists potently reduced the LC-induced hyperemic response (−56%, p < 0.001 or −47%, p < 0.05). Moreover, inhibition of astroglial metabolism (−35%, p < 0.01), vasoactive epoxyeicosatrienoic acids (EETs; −60%, p < 0.001) synthesis, large-conductance, calcium-operated (BK, −52%, p < 0.05), and inward-rectifier (Kir, −40%, p < 0.05) K+ channels primarily impaired the hyperemic response. The data demonstrate that LC stimulation recruits a broad network of cortical excitatory and inhibitory neurons resulting in increased cortical activity and that K+ fluxes and EET signaling mediate a large part of the hemodynamic response.