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• W3048475266 abstract "•We expressed DREADDs in the cholinergic neurons of the right basal forebrain (BFB)•We provide a tool to selectively modulate the default mode like network (DMLN)•Cholinergic stimulation decreases functional connectivity (FC) in the DMLN•Stimulation of right BFB induces lateralized effects on FC in DMLN and TPN The discovery of the default mode network (DMN), a large-scale brain network that is suppressed during attention-demanding tasks, had major impact in neuroscience. This network exhibits an antagonistic relationship with attention-related networks. A better understanding of the processes underlying modulation of DMN is imperative, as this network is compromised in several neurological diseases. Cholinergic neuromodulation is one of the major regulatory networks for attention, and studies suggest a role in regulation of the DMN. In this study, we unilaterally activated the right basal forebrain cholinergic neurons and observed decreased right intra-hemispheric and interhemispheric FC in the default mode like network (DMLN). Our findings provide critical insights into the interplay between cholinergic neuromodulation and DMLN, demonstrate that differential effects can be exerted between the two hemispheres by unilateral stimulation, and open windows for further studies involving directed modulations of DMN in treatments for diseases demonstrating compromised DMN activity. The discovery of the default mode network (DMN), a large-scale brain network that is suppressed during attention-demanding tasks, had major impact in neuroscience. This network exhibits an antagonistic relationship with attention-related networks. A better understanding of the processes underlying modulation of DMN is imperative, as this network is compromised in several neurological diseases. Cholinergic neuromodulation is one of the major regulatory networks for attention, and studies suggest a role in regulation of the DMN. In this study, we unilaterally activated the right basal forebrain cholinergic neurons and observed decreased right intra-hemispheric and interhemispheric FC in the default mode like network (DMLN). Our findings provide critical insights into the interplay between cholinergic neuromodulation and DMLN, demonstrate that differential effects can be exerted between the two hemispheres by unilateral stimulation, and open windows for further studies involving directed modulations of DMN in treatments for diseases demonstrating compromised DMN activity. An important finding in neuroscience during the last couple of decades was the discovery of the default mode network (DMN), which is a large-scale network of brain areas that are co-activated during passive mental processes and suppressed during externally oriented attention-demanding cognitive tasks. This was initially observed by Shulman et al., 1997Shulman G.L. Fiez J.A. Corbetta M. Buckner R.L. Miezin F.M. Raichle M.E. Petersen S.E. Common blood flow changes across visual tasks: II. Decreases in cerebral cortex.J. Cogn. Neurosci. 1997; 9: 648-663Crossref PubMed Scopus (1483) Google Scholar in a meta-analysis of nine positron emission tomography (PET) studies. In that study, the authors showed that several brain areas, including the medial prefrontal cortex, posterior cingulate cortex, and lateral parietal and temporal cortices, consistently increased their metabolic activity during states of rest or quiet wakefulness (Shulman et al., 1997Shulman G.L. Fiez J.A. Corbetta M. Buckner R.L. Miezin F.M. Raichle M.E. Petersen S.E. Common blood flow changes across visual tasks: II. Decreases in cerebral cortex.J. Cogn. Neurosci. 1997; 9: 648-663Crossref PubMed Scopus (1483) Google Scholar). Functional imaging studies, which followed, reported that the low-frequency activity fluctuations of these areas were highly temporally correlated, forming a set of intrinsically functionally connected brain areas currently known as the default mode network (DMN) (Greicius et al., 2003Greicius M.D. Krasnow B. Reiss A.L. Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis.Proc. Natl. Acad. Sci. U S A. 2003; 100: 253-258Crossref PubMed Scopus (4879) Google Scholar; Raichle et al., 2001Raichle M.E. Macleod A.M. Snyder A.Z. Powers W.J. Gusnard D.A. Shulman G.L. A default mode of brain function.Proc. Natl. Acad. Sci. U S A. 2001; 98: 676-682Crossref PubMed Scopus (9041) Google Scholar; Raichle and Snyder, 2007Raichle M.E. Snyder A.Z. A default mode of brain function: a brief history of an evolving idea.Neuroimage. 2007; 37 (discussion 1097-9): 1083-1090Crossref PubMed Scopus (1653) Google Scholar). The DMN has been associated with spontaneous internally directed cognitive processes such as mind wandering, self-oriented processes, and introspection (Andrews-Hanna et al., 2010Andrews-Hanna J.R. Reidler J.S. Huang C. Buckner R.L. Evidence for the default network's role in spontaneous cognition.J. Neurophysiol. 2010; 104: 322-335Crossref PubMed Scopus (467) Google Scholar; Buckner and Carroll, 2007Buckner R.L. Carroll D.C. Self-projection and the brain.Trends Cogn. Sci. 2007; 11: 49-57Abstract Full Text Full Text PDF PubMed Scopus (1869) Google Scholar). Disruption of DMN functioning has been linked to several neurological disorders, including attention deficit hyperactivity disorder (Tian et al., 2006Tian L. Jiang T. Wang Y. Zang Y. He Y. Liang M. Sui M. Cao Q. Hu S. Peng M. Zhuo Y. Altered resting-state functional connectivity patterns of anterior cingulate cortex in adolescents with attention deficit hyperactivity disorder.Neurosci. Lett. 2006; 400: 39-43Crossref PubMed Scopus (339) Google Scholar), mood disorders (Greicius et al., 2007Greicius M.D. Flores B.H. Menon V. Glover G.H. Solvason H.B. Kenna H. Reiss A.L. Schatzberg A.F. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus.Biol. Psychiatry. 2007; 62: 429-437Abstract Full Text Full Text PDF PubMed Scopus (1653) Google Scholar), epilepsy (Laufs et al., 2007Laufs H. Hamandi K. Salek-Haddadi A. Kleinschmidt A.K. Duncan J.S. Lemieux L. Temporal lobe interictal epileptic discharges affect cerebral activity in default mode brain regions.Hum. Brain Mapp. 2007; 28: 1023-1032Crossref PubMed Scopus (242) Google Scholar), Alzheimer's disease (Greicius et al., 2004Greicius M.D. Srivastava G. Reiss A.L. Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI.Proc. Natl. Acad. Sci. U S A. 2004; 101: 4637-4642Crossref PubMed Scopus (2870) Google Scholar) and others (Broyd et al., 2009Broyd S.J. Demanuele C. Debener S. Helps S.K. James C.J. Sonuga-Barke E.J. Default-mode brain dysfunction in mental disorders: a systematic review.Neurosci. Biobehav Rev. 2009; 33: 279-296Crossref PubMed Scopus (1236) Google Scholar). Upon the discovery of the DMN in humans, a default mode like network (DMLN) has been observed in several other mammalian species, such as the macaque monkey (Vincent et al., 2007Vincent J.L. Patel G.H. Fox M.D. Snyder A.Z. Baker J.T. van Essen D.C. Zempel J.M. Snyder L.H. Corbetta M. Raichle M.E. Intrinsic functional architecture in the anaesthetized monkey brain.Nature. 2007; 447: 83-86Crossref PubMed Scopus (1390) Google Scholar), rat (Lu et al., 2012Lu H. Zou Q. Gu H. Raichle M.E. Stein E.A. Yang Y. Rat brains also have a default mode network.Proc. Natl. Acad. Sci. U S A. 2012; 109: 3979-3984Crossref PubMed Scopus (392) Google Scholar), and mouse (Stafford et al., 2014Stafford J.M. Jarrett B.R. Miranda-Dominguez O. Mills B.D. Cain N. Mihalas S. Lahvis G.P. Lattal K.M. Mitchell S.H. David S.V. et al.Large-scale topology and the default mode network in the mouse connectome.Proc. Natl. Acad. Sci. U S A. 2014; 111: 18745-18750Crossref PubMed Scopus (151) Google Scholar). In rodents, DMLN consists of the following brain regions: orbital cortex, prelimbic cortex, cingulate cortex, auditory/temporal association cortex, posterior parietal cortex, retrosplenial cortex, and hippocampus (Lu et al., 2012Lu H. Zou Q. Gu H. Raichle M.E. Stein E.A. Yang Y. Rat brains also have a default mode network.Proc. Natl. Acad. Sci. U S A. 2012; 109: 3979-3984Crossref PubMed Scopus (392) Google Scholar; Stafford et al., 2014Stafford J.M. Jarrett B.R. Miranda-Dominguez O. Mills B.D. Cain N. Mihalas S. Lahvis G.P. Lattal K.M. Mitchell S.H. David S.V. et al.Large-scale topology and the default mode network in the mouse connectome.Proc. Natl. Acad. Sci. U S A. 2014; 111: 18745-18750Crossref PubMed Scopus (151) Google Scholar). Multiple studies observed shared features of the DMN in humans and the DMLN in rodents, i.e., its anatomical homology (Lu et al., 2012Lu H. Zou Q. Gu H. Raichle M.E. Stein E.A. Yang Y. Rat brains also have a default mode network.Proc. Natl. Acad. Sci. U S A. 2012; 109: 3979-3984Crossref PubMed Scopus (392) Google Scholar), its link with brain disorders (Sforazzini et al., 2016Sforazzini F. Bertero A. Dodero L. David G. Galbusera A. Scattoni M.L. Pasqualetti M. Gozzi A. Altered functional connectivity networks in acallosal and socially impaired BTBR mice.Brain Struct. Funct. 2016; 221: 941-954Crossref PubMed Scopus (54) Google Scholar; Anckaerts et al., 2019Anckaerts C. Blockx I. Summer P. Michael J. Hamaide J. Kreutzer C. Boutin H. Couillard-Despres S. Verhoye M. van der Linden A. Early functional connectivity deficits and progressive microstructural alterations in the TgF344-AD rat model of Alzheimer's Disease: a longitudinal MRI study.Neurobiol. Dis. 2019; 124: 93-107Crossref PubMed Scopus (29) Google Scholar; Shah et al., 2016Shah D. Praet J. Latif Hernandez A. Hofling C. Anckaerts C. Bard F. Morawski M. Detrez J.R. Prinsen E. Villa A. et al.Early pathologic amyloid induces hypersynchrony of BOLD resting-state networks in transgenic mice and provides an early therapeutic window before amyloid plaque deposition.Alzheimers Dement. 2016; 12: 964-976Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar), its decreased activity during tasks in comparison with rest (Hinz et al., 2019Hinz R. Peeters L.M. Shah D. Missault S. Belloy M. Vanreusel V. Malekzadeh M. Verhoye M. van der Linden A. Keliris G.A. Bottom-up sensory processing can induce negative BOLD responses and reduce functional connectivity in nodes of the default mode-like network in rats.Neuroimage. 2019; 197: 167-176Crossref PubMed Scopus (6) Google Scholar; Rohleder et al., 2016Rohleder C. Wiedermann D. Neumaier B. Drzezga A. Timmermann L. Graf R. Leweke F.M. Endepols H. The functional networks of prepulse inhibition: neuronal connectivity analysis based on FDG-PET in awake and unrestrained rats.Front. Behav. Neurosci. 2016; 10: 148Crossref PubMed Scopus (38) Google Scholar) and its anti-correlation with task-positive networks (TPNs) (Schwarz et al., 2013Schwarz A.J. Gass N. Sartorius A. Risterucci C. Spedding M. Schenker E. Meyer-Lindenberg A. Weber-Fahr W. Anti-correlated cortical networks of intrinsic connectivity in the rat brain.Brain Connect. 2013; 3: 503-511Crossref PubMed Scopus (42) Google Scholar; Belloy et al., 2018Belloy M.E. Naeyaert M. Abbas A. Shah D. Vanreusel V. van Audekerke J. Keilholz S.D. KELIRIS G.A. van der Linden A. Verhoye M. Dynamic resting state fMRI analysis in mice reveals a set of Quasi-Periodic Patterns and illustrates their relationship with the global signal.Neuroimage. 2018; 180: 463-484Crossref PubMed Scopus (34) Google Scholar). The DMN has also been described as a “task-negative network,” which exhibits anti-correlations with “task-positive networks” (Greicius et al., 2003Greicius M.D. Krasnow B. Reiss A.L. Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis.Proc. Natl. Acad. Sci. U S A. 2003; 100: 253-258Crossref PubMed Scopus (4879) Google Scholar; Fox et al., 2005Fox M.D. Snyder A.Z. Vincent J.L. Corbetta M. van Essen D.C. Raichle M.E. The human brain is intrinsically organized into dynamic, anticorrelated functional networks.Proc. Natl. Acad. Sci. U S A. 2005; 102: 9673-9678Crossref PubMed Scopus (6173) Google Scholar; Belloy et al., 2018Belloy M.E. Naeyaert M. Abbas A. Shah D. Vanreusel V. van Audekerke J. Keilholz S.D. KELIRIS G.A. van der Linden A. Verhoye M. Dynamic resting state fMRI analysis in mice reveals a set of Quasi-Periodic Patterns and illustrates their relationship with the global signal.Neuroimage. 2018; 180: 463-484Crossref PubMed Scopus (34) Google Scholar). The antagonistic interaction between the DMN and top-down attentional processes has been observed repeatedly in humans (Buckner and Dinicola, 2019Buckner R.L. Dinicola L.M. The brain's default network: updated anatomy, physiology and evolving insights.Nat. Rev. Neurosci. 2019; 20: 593-608Crossref PubMed Scopus (351) Google Scholar); however, the underlying mechanisms remain poorly understood. A number of previous studies have shown that the extent and the magnitude of the task-induced decreases in BOLD responses within the DMN vary with the difficulty of the cognitive tasks and that task performance is positively correlated with the strength of the DMN suppression (Rajan et al., 2019Rajan A. Meyyappan S. Walker H. Henry Samuel I.B. Hu Z. Ding M. Neural mechanisms of internal distraction suppression in visual attention.Cortex. 2019; 117: 77-88Crossref PubMed Scopus (9) Google Scholar; Ossandon et al., 2011Ossandon T. Jerbi K. Vidal J.R. Bayle D.J. Henaff M.A. Jung J. Minotti L. Bertrand O. Kahane P. Lachaux J.P. Transient suppression of broadband gamma power in the default-mode network is correlated with task complexity and subject performance.J. Neurosci. 2011; 31: 14521-14530Crossref PubMed Scopus (149) Google Scholar; Wen et al., 2013Wen X. Liu Y. Yao L. Ding M. Top-down regulation of default mode activity in spatial visual attention.J. Neurosci. 2013; 33: 6444-6453Crossref PubMed Scopus (100) Google Scholar; Mayer et al., 2010Mayer J.S. Roebroeck A. Maurer K. Linden D.E. Specialization in the default mode: task-induced brain deactivations dissociate between visual working memory and attention.Hum. Brain Mapp. 2010; 31: 126-139PubMed Google Scholar; Singh and Fawcett, 2008Singh K.D. Fawcett I.P. Transient and linearly graded deactivation of the human default-mode network by a visual detection task.Neuroimage. 2008; 41: 100-112Crossref PubMed Scopus (223) Google Scholar). Another important feature of the DMN, demonstrated by several human studies, is decreased functional connectivity (FC) within the network during the performance of cognitive tasks (Gao et al., 2013Gao W. Gilmore J.H. Alcauter S. Lin W. The dynamic reorganization of the default-mode network during a visual classification task.Front. Syst. Neurosci. 2013; 7: 34Crossref PubMed Scopus (31) Google Scholar; Fransson, 2006Fransson P. How default is the default mode of brain function? Further evidence from intrinsic BOLD signal fluctuations.Neuropsychologia. 2006; 44: 2836-2845Crossref PubMed Scopus (492) Google Scholar). Interestingly, a recent study in humans demonstrated that the presentation of random flashing checkerboard visual stimuli can induce negative BOLD responses in DMN brain regions (Razlighi, 2018Razlighi Q.R. Task-evoked negative BOLD response in the default mode network Does not alter its functional connectivity.Front. Comput. Neurosci. 2018; 12: 67Crossref PubMed Scopus (5) Google Scholar). Similarly, our group evaluated the BOLD responses in the DMLN regions upon the presentation of continuous flickering visual stimuli in sedated rats. We demonstrated that this visual stimulation paradigm could deactivate nodes of the DMLN and decrease the FC assimilating earlier studies in humans (Hinz et al., 2019Hinz R. Peeters L.M. Shah D. Missault S. Belloy M. Vanreusel V. Malekzadeh M. Verhoye M. van der Linden A. Keliris G.A. Bottom-up sensory processing can induce negative BOLD responses and reduce functional connectivity in nodes of the default mode-like network in rats.Neuroimage. 2019; 197: 167-176Crossref PubMed Scopus (6) Google Scholar). Recent studies have demonstrated that the basal forebrain (BFB) is a key player in modulating oscillations in the prefrontal cortex during behaviors aligned with DMN activation and de-activation patterns, such as moving from the home cage to an experimental arena where exploration of the environment is enhanced, and suggested these findings are consistent with BFB exerting control of large-scale functional networks such as the DMN (Nair et al., 2018Nair J. Klaassen A.L. Arato J. Vyssotski A.L. Harvey M. Rainer G. Basal forebrain contributes to default mode network regulation.Proc. Natl. Acad. Sci. U S A. 2018; 115: 1352-1357Crossref PubMed Scopus (38) Google Scholar). This hypothesis is also consistent with evidence that cholinergic neurons originating from the BFB are strongly involved in attentional processes, specifically the projections from the diagonal band of Broca, substantia innominata, and the nucleus Basalis of Meynert (NBM) to the cortex (Ballinger et al., 2016Ballinger E.C. Ananth M. Talmage D.A. Role L.W. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline.Neuron. 2016; 91: 1199-1218Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar; Bloem et al., 2014Bloem B. Schoppink L. Rotaru D.C. Faiz A. Hendriks P. Mansvelder H.D. van de Berg W.D. Wouterlood F.G. Topographic mapping between basal forebrain cholinergic neurons and the medial prefrontal cortex in mice.J. Neurosci. 2014; 34: 16234-16246Crossref PubMed Scopus (81) Google Scholar; Howe et al., 2017Howe W.M. Gritton H.J. Lusk N.A. Roberts E.A. Hetrick V.L. Berke J.D. Sarter M. Acetylcholine release in prefrontal cortex promotes gamma oscillations and theta-gamma coupling during cue detection.J. Neurosci. 2017; 37: 3215-3230Crossref PubMed Scopus (69) Google Scholar; Parikh et al., 2007Parikh V. Kozak R. Martinez V. Sarter M. Prefrontal acetylcholine release controls cue detection on multiple timescales.Neuron. 2007; 56: 141-154Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar). These projections induce acute increases of acetylcholine (ACh) in the medial prefrontal cortex, which mediate cue detection and are necessary for successful task performance (Howe et al., 2017Howe W.M. Gritton H.J. Lusk N.A. Roberts E.A. Hetrick V.L. Berke J.D. Sarter M. Acetylcholine release in prefrontal cortex promotes gamma oscillations and theta-gamma coupling during cue detection.J. Neurosci. 2017; 37: 3215-3230Crossref PubMed Scopus (69) Google Scholar; Gritton et al., 2016Gritton H.J. Howe W.M. Mallory C.S. Hetrick V.L. Berke J.D. Sarter M. Cortical cholinergic signaling controls the detection of cues.Proc. Natl. Acad. Sci. U S A. 2016; 113: E1089-E1097Crossref PubMed Scopus (110) Google Scholar; Parikh et al., 2007Parikh V. Kozak R. Martinez V. Sarter M. Prefrontal acetylcholine release controls cue detection on multiple timescales.Neuron. 2007; 56: 141-154Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar). Moreover, ACh enhances visual processing by inducing cortical decorrelation and desynchronization in sensory cortices, which increases the signal to noise ratio (Chen et al., 2015Chen N. Sugihara H. Sur M. An acetylcholine-activated microcircuit drives temporal dynamics of cortical activity.Nat. Neurosci. 2015; 18: 892-902Crossref PubMed Scopus (118) Google Scholar; Nguyen et al., 2015Nguyen H.N. Huppe-Gourgues F. Vaucher E. Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections.Front. Syst. Neurosci. 2015; 9: 1Crossref PubMed Scopus (7) Google Scholar; Pinto et al., 2013Pinto L. Goard M.J. Estandian D. Xu M. Kwan A.C. Lee S.H. Harrison T.C. Feng G. Dan Y. Fast modulation of visual perception by basal forebrain cholinergic neurons.Nat. Neurosci. 2013; 16: 1857-1863Crossref PubMed Scopus (332) Google Scholar). Moreover, the BFB has been implicated in cortical network switching between brain states by exerting direct and/or indirect control to the prefrontal cortex (Espinosa et al., 2019bEspinosa N. Alonso A. Morales C. Espinosa P. Chavez A.E. Fuentealba P. Basal forebrain gating by somatostatin neurons drives prefrontal cortical activity.Cereb. Cortex. 2019; 29: 42-53Crossref PubMed Scopus (11) Google Scholar; Li et al., 2015Li W. Motelow J.E. Zhan Q. Hu Y.C. Kim R. Chen W.C. Blumenfeld H. Cortical network switching: possible role of the lateral septum and cholinergic arousal.Brain Stimul. 2015; 8: 36-41Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). This evidence suggested an involvement of the BFB cholinergic system in the up- and down-regulation of the DMN and its anti-correlation with task-based/attention-related networks. Thus, we hypothesized that specific stimulation of cholinergic neurons in the BFB can influence the functional connectivity (FC) in the DMLN of rats as measured with whole-brain measures of activity and connectivity such as resting-state (rs) fMRI, which can directly visualize the complete DMN and task-based networks. Furthermore, inspired by a recent study in rhesus macaques that demonstrated unilateral suppression of cortical fluctuations ipsilateral to pharmacological inactivations in the NBM (Turchi et al., 2018Turchi J. Chang C. Ye F.Q. Russ B.E. Yu D.K. Cortes C.R. Monosov I.E. Duyn J.H. Leopold D.A. The basal forebrain regulates global resting-state fMRI fluctuations.Neuron. 2018; 97: 940-952 e4Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), we hypothesized that unilateral activations of cholinergic neurons in homologous areas in the rat could potentially lead to asymmetric changes to the DMLN that could be beneficial in the treatment of certain neurological syndromes that are thought to stem from hemispheric imbalances in attentional processes such as hemispatial neglect (Bartolomeo et al., 2012Bartolomeo P. Thiebaut de Schotten M. Chica A.B. Brain networks of visuospatial attention and their disruption in visual neglect.Front. Hum. Neurosci. 2012; 6: 110Crossref PubMed Scopus (115) Google Scholar). To this end, we combined functional MRI with designer receptors exclusively activated by designer drugs (DREADDs) to selectively increase the neuronal firing in basal forebrain (BFB) cholinergic neurons and study their effects in whole brain networks with a particular focus on the DMLN. We found that unilateral cholinergic activation in the right BFB resulted in decreased FC in the DMLN and the effect showed significant laterality in specific connections in the DMLN and task-based networks. The results of this study directly demonstrate the effects of cholinergic neuromodulation in the DMLN in rats and open windows for further studies that could use directed modulations of DMLN in rehabilitation treatments for diseases demonstrating compromised DMN activity. Chemogenetic tools, such as DREADDs, allow control of the activity of selectively targeted neuronal populations (Alexander et al., 2009Alexander G.M. Rogan S.C. Abbas A.I. Armbruster B.N. Pei Y. Allen J.A. Nonneman R.J. Hartmann J. Moy S.S. Nicolelis M.A. et al.Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors.Neuron. 2009; 63: 27-39Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar). In our study, excitatory DREADDs were used to increase the activity of cholinergic neurons in the right BFB. To ensure exclusive DREADDs expression in the cholinergic neurons of the right BFB, we used ChAT-Cre transgenic rats that selectively express Cre-recombinase in all choline acetyltransferase (ChAT)-expressing neurons, i.e., cholinergic neurons (Witten et al., 2011Witten I.B. Steinberg E.E. Lee S.Y. Davidson T.J. Zalocusky K.A. Brodsky M. Yizhar O. Cho S.L. Gong S. Ramakrishnan C. et al.Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement.Neuron. 2011; 72: 721-733Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar). The presence of Cre-recombinase allows the conversion of the inverted DNA constructs, so that gene transcription can take place. Viral vectors containing inverted DNA constructs encoding DREADDs were stereotactically injected in the right BFB (Figure 1). Since cholinergic neurons in the anterior medial portion of the BFB have been shown to project to the medial and frontal cortex, and have been implicated to play a role in attention, these medial nuclei were targeted during the stereotactic surgery (Ballinger et al., 2016Ballinger E.C. Ananth M. Talmage D.A. Role L.W. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline.Neuron. 2016; 91: 1199-1218Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar; Chaves-Coira et al., 2018Chaves-Coira I. Martin-Cortecero J. Nunez A. Rodrigo-Angulo M.L. Basal forebrain nuclei display distinct projecting pathways and functional circuits to sensory primary and prefrontal cortices in the rat.Front. Neuroanat. 2018; 12: 69Crossref PubMed Scopus (19) Google Scholar). Immunohistochemical experiments were performed on eight animals to validate transfection of cholinergic neurons in the target region. The DREADDs were tagged with a fluorescent label (m-Cherry), which could be observed in the targeted medial nuclei of the basal forebrain, namely, the horizontal diagonal band of Broca, substantia innominata, and nucleus basalis of Meynert. Dual visualization of mCherry and ChAT, which is a specific marker for cholinergic neurons via immunohistochemistry, revealed co-localization of mCherry and ChAT in the right BFB (Figure 1). These results indicated successful cell-type-specific transfection of the cholinergic neurons in the selected regions in the right BFB. First, the temporal profile of the DREADDs-induced FC changes within DMLN was evaluated. Regions of interest (ROIs) were drawn in brain regions of the DMLN in rats (Lu et al., 2012Lu H. Zou Q. Gu H. Raichle M.E. Stein E.A. Yang Y. Rat brains also have a default mode network.Proc. Natl. Acad. Sci. U S A. 2012; 109: 3979-3984Crossref PubMed Scopus (392) Google Scholar; Stafford et al., 2014Stafford J.M. Jarrett B.R. Miranda-Dominguez O. Mills B.D. Cain N. Mihalas S. Lahvis G.P. Lattal K.M. Mitchell S.H. David S.V. et al.Large-scale topology and the default mode network in the mouse connectome.Proc. Natl. Acad. Sci. U S A. 2014; 111: 18745-18750Crossref PubMed Scopus (151) Google Scholar), and their FC alterations were followed up over time after administration of clozapine-N-oxide (CNO). Significantly decreased FC in the right DMLN could be observed in the DREADDs-expressing rats starting at 5–10 min post-CNO injection (p = 0.002, Figure 2C). Furthermore, this significantly decreased FC in the DMLN lasted at least until 20 min post-CNO injection (10–15 min: p = 0.01; 15–20 min: p = 0.001, Figure 2C). In contrast, CNO injection in the sham group (p = 0.154) or saline injection in the DREADDs-expressing animals (5–10 min: p = 0.530; 10–15 min: p = 0.871; 15–20 min: p = 0.059) did not elicit FC alterations. To better understand the effect of right BFB stimulation on bilateral DMLN FC, an ROI-based analysis was performed using DMLN ROIs across the hemispheres. First, the FC of DMLN regions after CNO injection and saline injection was compared in the DREADDs-expressing group. The CNO and saline injections were performed in the same group of animals during different scan sessions. These results demonstrated that CNO-induced stimulation of the right BFB cholinergic system significantly decreased the FC between various DMLN ROI pairs (Figure 2D). Additionally, comparing the average intra-hemispheric and inter-hemispheric FC of the DMLN between both groups revealed significantly decreased FC within the right hemisphere (p = 0.002) as well as between the hemispheres (p = 0.007). Next to the evaluation of the FC within the DMLN, a seed-based analysis was performed for seed regions in the right Cg and right RSP to assess alterations of the FC patterns across the brain. These analyses revealed that right BFB stimulation significantly decreased the FC for both seed regions (Figures 3A–3D ). Furthermore, comparison of the DMLN FC between the sham group and the saline-injected DREADDs-expressing group showed no significant FC alterations (Figures S1A and S1B). Non-specific effects of CNO injection on the intra- and inter-hemispheric FC of the DMLN were evaluated by comparing the sham group with the DREADDs-expressing group after CNO injection. This analysis showed that the average FC in the right hemisphere and between both hemispheres significantly decreased only in the DREADDs-expressing rats (Figure S2). These results suggest that CNO injection did not induce non-specific effects on FC in the DMLN. Next to the evaluation of FC alterations in the DMLN, the resting-state neural activity alterations in the DMLN were assessed by comparing the fractional amplitude of low-frequency fluctuations (fALFF [Zou et al., 2008Zou Q.H. Zhu C.Z. Yang Y. Zuo X.N. Long X.Y. Cao Q.J. Wang Y.F. Zang Y.F. An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF.J. Neurosci. Methods. 2008; 172: 137-141Crossref PubMed Scopus (1228) Google Scholar]) values upon CNO injection and saline injection in the DREADDs-expressing group. In this analysis, fALFF values were extracted from voxels in a mask consisting of the mean group FC map of seed regions in the right Cg and right RSP (see Figures 3E–3H). These seed regions are key nodes of the DMLN in rats, and their FC maps were used as estimated masks of the DMLN FC. The obtained masks were divided into unilateral masks for the ipsilateral right hemisphere and for the contralateral left hemisphere. The extracted" @default.
• W3048475266 created "2020-08-18" @default.
• W3048475266 creator A5008950728 @default.
• W3048475266 creator A5033866580 @default.
• W3048475266 creator A5061113559 @default.
• W3048475266 creator A5067716651 @default.
• W3048475266 creator A5076030155 @default.
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• W3048475266 date "2020-09-01" @default.
• W3048475266 modified "2023-10-16" @default.
• W3048475266 title "Cholinergic Modulation of the Default Mode Like Network in Rats" @default.
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