BRAIN HEMODYNAMIC RESPONSE TO SOMATOSENSORY STIMULATION IN NEUROLIGIN-1 KNOCKOUT MICE E. BELANGER-NELSON, a,b M. FREYBURGER, a,b,c P. POULIOT, d E. BEAUMONT, b  F. LESAGE d AND V. MONGRAIN a,b,c * a Center for Advanced Research in Sleep Medicine, Ho ˆpital du Sacre ´-Coeur de Montre ´al, Montreal, QC, H4J 1C5, Canada b Research Center, Ho ˆpital du Sacre ´-Coeur de Montre ´al, Montreal, QC, H4J 1C5, Canada c Department of Neuroscience, Universite ´ de Montre ´al, Montreal, QC, H3C 3J7, Canada d Department of Electrical Engineering, E ´ cole Polytechnique de Montre ´al and Research Center, Montreal Heart Institute, Montreal, QC, H1T 1C8, Canada Abstract—Neuroligin 1 (NLGN1) is a postsynaptic adhesion molecule that determines N-methyl-D-aspartate receptor (NMDAR) function and cellular localization. Our recent work showed that Nlgn1 knockout (KO) mice cannot sustain neu- ronal activity occurring during wakefulness for a prolonged period of time. Since NMDAR-dependent neuronal activity drives an important vascular response, we used multispec- tral optical imaging to determine if the hemodynamic response to neuronal stimulation is modified in Nlgn1 KO mice. We observed that Nlgn1 KO mice show a 10% lower response rate to forepaw electrical stimulation compared to wild-type (WT) and heterozygote (HET) littermates on both the contra- and ipsilateral sides of the somatosensory cor- tex. Moreover, Nlgn1 mutant mice showed an earlier oxyhe- moglobin peak response that tended to return to baseline faster than in WT mice. Analysis of the time course of the hemodynamic response also showed that HET mice express a faster dynamics of cerebrovascular response in compari- son to WT. Taken together, these data are indicative of an altered immediate response of the brain to peripheral stimulation in Nlgn1 KO mice, and suggest a role for NLGN1 in the regulation of cerebrovascular responses. Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: multispectral intrinsic optical imaging, cerebrovascular response, N-methyl-D-aspartate receptors, synaptic adhesion molecules, rodents. INTRODUCTION The brain is one of the most oxygen-consuming organs because the oxidation of glucose provides the energy required for neuronal activity (Siesjo, 1978). Neuronal activity, oxygen consumption and metabolism are thus strongly linked together. Cerebral blood flow (CBF) regulates the oxygen supply to brain tissue and increases during neuronal activity (Uludag et al., 2004; Leithner et al., 2010). CBF typically increases within 1 s following electrical stimulation, along with other hemodynamic changes such as oxyhemoglobin (HbO) increases and deoxyhemoglobin (HbR) decreases (Dunn et al., 2005; Dubeau et al., 2011). Dysfunctions in the vascular response of the brain will impact neuronal activity and were shown to associate with cognitive impairment (Iadecola, 2013). Glutamate is the main excitatory neurotransmitter of the brain (Nicholls, 1992; Attwell and Laughlin, 2001). Glutamatergic neurotransmission thus represents an important energy-consuming process (Attwell and Iadecola, 2002). The hemodynamic response to somato- sensory stimulation has been shown to depend on the activity of a-amino-3-hydroxy-5-methyl-4-isoxazoleprop- ionic acid and N-methyl-D-aspartate receptors (AMPAR and NMDAR) (Gsell et al., 2006). More precisely, blocking NMDAR and AMPAR not only modulates synaptic responses but also alters CBF in the rat somatosensory cortex (Norup Nielsen and Lauritzen, 2001). Also, a selective NMDAR antagonist was shown to block the cerebral dilator response induced by NMDA in rodents (Faraci and Breese, 1994; Pelligrino et al., 1995, 1996). Specific adhesion proteins could mediate the relationship between cerebrovascular response and glutamatergic neurotransmission. Indeed, members of both the Ephrin/Eph and Neurexin/Neuroligin (NRXN/ NLGN) families have been linked to neurovascular physiology. For instance, the absence of EphA4 led to smaller diameter brain blood vessels (Goldshmit et al., 2006), whereas NRXN and NLGN were shown to be expressed in blood vessels and to modulate angiogenesis (Bottos et al., 2009; Graziano et al., 2013). NLGN1 is a post-synaptic protein that regulates synaptic function through its association with pre-synaptic NRXN (Ichtchenko et al., 1995). NLGN1 has been shown to regulate NMDAR functioning and sub-cellular localization (Kim et al., 2008; Barrow et al., 2009; Wittenmayer et al., 2009; Jung et al., 2010). Recent work shows that Nlgn1 knockout (KO) mice exhibit deficits in social novelty and http://dx.doi.org/10.1016/j.neuroscience.2014.12.069 0306-4522/Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved. * Correspondence to: V. Mongrain, Centre for Advanced Research in Sleep Medicine, Hoˆpital du Sacre´-Coeur de Montre´al, 5400 Gouin West Boulevard, Montreal, QC, H4J 1C5, Canada. Tel: +1-514-338- 2222x3323. E-mail address: valerie.mongrain@umontreal.ca (V. Mongrain).   Present address: Department of Biomedical Sciences, East Ten- nessee State University, Johnson City, TN 37614, United States. Abbreviations: ANOVA, analysis of variance; CBF, cerebral blood flow; EEG, electroencephalographic; HbO, oxyhemoglobin; HbR, deoxyhemoglobin; HET, heterozygote; KO, knockout; LED, light- emitting diode; LTP, long-term potentiation; NMDAR, N-methyl-D- aspartate receptor; NRXN, Neurexin; NLGN, Neuroligin; NLGN1, Neuroligin 1; NLGN3, Neuroligin 3; ROI, region of interest; SEM, standard error of the mean; WT, wild-type. Neuroscience 289 (2015) 242–250 242