title: Bidirectional Control of Anxiety-Related Behaviors in Mice: Role of Inputs Arising from the Ventral Hippocampus to the Lateral Septum and Medial Prefrontal Cortex.
abstract: Anxiety is an adaptive response to potentially threatening situations. Exaggerated and uncontrolled anxiety responses become maladaptive and lead to anxiety disorders. Anxiety is shaped by a network of forebrain structures, including the hippocampus, septum, and prefrontal cortex. In particular, neural inputs arising from the ventral hippocampus (vHPC) to the lateral septum (LS) and medial prefrontal cortex (mPFC) are thought to serve as principal components of the anxiety circuit. However, the role of vHPC-to-LS and vHPC-to-mPFC signals in anxiety is unclear, as no study has directly compared their behavioral contribution at circuit level. We targeted LS-projecting vHPC cells and mPFC-projecting vHPC cells by injecting the retrogradely propagating canine adenovirus encoding Cre recombinase into the LS or mPFC, and injecting a Cre-responsive AAV (AAV8-hSyn-FLEX-hM3D or hM4D) into the vHPC. Consequences of manipulating these neurons were examined in well-established tests of anxiety. Chemogenetic manipulation of LS-projecting vHPC cells led to bidirectional changes in anxiety: activation of LS-projecting vHPC cells decreased anxiety whereas inhibition of these cells produced opposite anxiety-promoting effects. The observed anxiety-reducing function of LS-projecting cells was in contrast with the function of mPFC-projecting cells, which promoted anxiety. In addition, double retrograde tracing demonstrated that LS- and mPFC-projecting cells represent two largely anatomically distinct cell groups. Altogether, our findings suggest that the vHPC houses discrete populations of cells that either promote or suppress anxiety through differences in their projection targets. Disruption of the intricate balance in the activity of these two neuron populations may drive inappropriate behavioral responses seen in anxiety disorders.
authors.affiliation: Department of Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: Gustavo Morrone
authors.initials: GM
authors.lastname: Parfitt
authors.affiliation: Department of Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Nguyen
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, ON, Canada.
authors.forename: Jee Yoon
authors.initials: JY
authors.lastname: Bang
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, ON, Canada.
authors.forename: Afif J
authors.identifier: http://orcid.org/0000-0001-7549-5202
authors.initials: AJ
authors.lastname: Aqrabawi
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, ON, Canada.|Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON, Canada.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Tran
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, ON, Canada.|Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON, Canada.
authors.forename: D Kanghoon
authors.initials: DK
authors.lastname: Seo
authors.affiliation: Department of Cell &Systems Biology, University of Toronto, Toronto, ON, Canada.|Department of Biological Sciences, University of Toronto Scarborough, Toronto, ON, Canada.|Learning in Machines and Brains Program, Canadian Institute for Advanced Research, Toronto, ON, Canada.
authors.forename: Blake A
authors.initials: BA
authors.lastname: Richards
authors.affiliation: Department of Psychology, University of Toronto, Toronto, ON, Canada.|Department of Cell &Systems Biology, University of Toronto, Toronto, ON, Canada.
authors.forename: Jun Chul
authors.initials: JC
authors.lastname: Kim
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001522:Behavior, Animal / Q000502:physiology; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D009434:Neural Pathways / Q000502:physiology; D056347:Neuroanatomical Tract-Tracing Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D012686:Septal Nuclei / Q000187:drug effects / Q000502:physiology*
chemical_list: D003024:Clozapine; C079149:clozapine N-oxide