title: Chemogenetic Inactivation of Dorsal Anterior Cingulate Cortex Neurons Disrupts Attentional Behavior in Mouse.
abstract: Attention is disrupted commonly in psychiatric disorders, yet mechanistic insight remains limited. Deficits in this function are associated with dorsal anterior cingulate cortex (dACC) excitotoxic lesions and pharmacological disinhibition; however, a causal relationship has not been established at the cellular level. Moreover, this association has not yet been examined in a genetically tractable species such as mice. Here, we reveal that dACC neurons causally contribute to attention processing by combining a chemogenetic approach that reversibly suppresses neural activity with a translational, touchscreen-based attention task in mice. We virally expressed inhibitory hM4Di DREADD (designer receptor exclusively activated by a designer drug) in dACC neurons, and examined the effects of this inhibitory action with the attention-based five-choice serial reaction time task. DREADD inactivation of the dACC neurons during the task significantly increased omission and correct response latencies, indicating that the neuronal activities of dACC contribute to attention and processing speed. Selective inactivation of excitatory neurons in the dACC not only increased omission, but also decreased accuracy. The effect of inactivating dACC neurons was selective to attention as response control, motivation, and locomotion remain normal. This finding suggests that dACC excitatory neurons play a principal role in modulating attention to task-relevant stimuli. This study establishes a foundation to chemogenetically dissect specific cell-type and circuit mechanisms underlying attentional behaviors in a genetically tractable species.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Demars
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Short
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Nabel
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Baxter
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Hirofumi
authors.identifier: http://orcid.org/0000-0002-1045-1337
authors.initials: H
authors.lastname: Morishita
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018756:GABA Antagonists / Q000008:administration & dosage; D005822:Genetic Vectors; D006179:Gyrus Cinguli / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010433:Pentylenetetrazole / Q000008:administration & dosage; D011930:Reaction Time; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D018756:GABA Antagonists; D043588:Receptor, Muscarinic M4; D003024:Clozapine; C079149:clozapine N-oxide; D010433:Pentylenetetrazole