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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 (&gt;36%) of interneurons that colocalize parvalbumin, somatostatin, or nitric oxide synthase compared with pyramidal cells expressing cyclooxygenase-2 (22%, p &lt; 0.05) or vasoactive intestinal polypeptide-containing interneurons (16%, p &lt; 0.01). Concurrently, LC stimulation elicited larger ipsilateral compared with contralateral increases in cortical CBF (52 vs 31%, p &lt; 0.01). These CBF responses were almost abolished (-70%, p &lt; 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 &lt; 0.001 and -30%, p &lt; 0.05, respectively). Blockade of glutamatergic or GABAergic neurotransmission with NMDA or GABA(A) receptor antagonists potently reduced the LC-induced hyperemic response (-56%, p &lt; 0.001 or -47%, p &lt; 0.05). Moreover, inhibition of astroglial metabolism (-35%, p &lt; 0.01), vasoactive epoxyeicosatrienoic acids (EETs; -60%, p &lt; 0.001) synthesis, large-conductance, calcium-operated (BK, -52%, p &lt; 0.05), and inward-rectifier (Kir, -40%, p &lt; 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.

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