Distinct neural pathways mediate α7 nicotinic acetylcholine receptor-dependent activation of the forebrain.
alpha(7) nicotinic acetylcholine receptor (nAChR) agonists are candidates for the treatment of cognitive deficits in schizophrenia. Selective alpha(7) nAChR agonists, such as SSR180711, activate neurons in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (ACCshell) in rats, regions important for cognitive function. However, the neural substrates involved in these effects remain elusive. Here we identify cortically projecting cholinergic neurons in the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain (BF) as important targets for alpha(7) nAChR activation, as measured by c-Fos immunoreactivity, a marker of neuronal activation. Selective depletion of these cholinergic neurons abolishes the SSR180711-induced activation of the mPFC but not the ACCshell, demonstrating their critical importance for alpha(7) nAChR-dependent activation of the mPFC. Contrarily, selective depletion of dopaminergic neurons in the ventral tegmental area abolishes the SSR180711-induced activation of the ACCshell but not the mPFC or HDB. These results demonstrate 2 distinct neural pathways activated by SSR180711. The BF and mPFC are important for attentional function and may subserve the procognitive effects of alpha(7) nAChR agonists, whereas activation of the ACCshell is implicated in the beneficial effect of antipsychotics on the positive symptoms of schizophrenia.
Thomsen
Morten S
MS
Neurobiology Research Unit, Copenhagen University Hospital, DK2100 Copenhagen, Denmark. morten@nru.dk
Hay-Schmidt
Anders
A
Hansen
Henrik H
HH
Mikkelsen
Jens D
JD
D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000502:physiology*; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D015415:Biomarkers; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D016760:Proto-Oncogene Proteins c-fos; D011978:Receptors, Nicotinic; C516833:SSR180711; D064569:alpha7 Nicotinic Acetylcholine Receptor