ABSTRACT
Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.
Subject(s)
Behavioral Symptoms/drug therapy , Behavioral Symptoms/pathology , Carbazoles/therapeutic use , Hippocampus/pathology , Neurogenesis/drug effects , Neuroprotective Agents/therapeutic use , Animals , Antidepressive Agents/therapeutic use , Behavioral Symptoms/genetics , Behavioral Symptoms/physiopathology , Caloric Restriction , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cranial Irradiation , Disease Models, Animal , Ki-67 Antigen/metabolism , Male , Mice , Mice, Inbred C57BL , Neurogenesis/genetics , Neurogenesis/radiation effects , Neurons/drug effects , Neurons/radiation effects , Phosphopyruvate Hydratase/metabolism , Receptors, Ghrelin/deficiency , Receptors, Ghrelin/genetics , Swimming/psychology , Time FactorsABSTRACT
Neuronal PAS domain protein 2 (NPAS2) is a basic helix-loop-helix (bHLH) PAS domain transcription factor expressed in multiple regions of the vertebrate brain. Targeted insertion of a beta-galactosidase reporter gene (lacZ) resulted in the production of an NPAS2-lacZ fusion protein and an altered form of NPAS2 lacking the bHLH domain. The neuroanatomical expression pattern of NPAS2-lacZ was temporally and spatially coincident with formation of the mature frontal association/limbic forebrain pathway. NPAS2-deficient mice were subjected to a series of behavioral tests and were found to exhibit deficits in the long-term memory arm of the cued and contextual fear task. Thus, NPAS2 may serve a dedicated regulatory role in the acquisition of specific types of memory.
Subject(s)
Brain/physiology , Learning/physiology , Memory/physiology , Nerve Tissue Proteins/physiology , Transcription Factors/physiology , Animals , Avoidance Learning , Basic Helix-Loop-Helix Transcription Factors , Behavior, Animal , Brain/metabolism , Conditioning, Psychological , Cues , Fear , Gene Targeting , Helix-Loop-Helix Motifs , Limbic System/metabolism , Limbic System/physiology , Male , Mice , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Prosencephalon/metabolism , Prosencephalon/physiology , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Touch , Transcription Factors/chemistry , Transcription Factors/genetics , Transcriptional Activation , Transfection , beta-Galactosidase/metabolismABSTRACT
A marker assisted selection protocol is presented that allows for the generation of congenic or consomic strains derived from a C57BL/6J:129S6/SvEvTac mixed strain background. The protocol uses defined primer pairs to generate amplicons that can be distinguished by non-denaturing agarose electrophoresis. Use of this application should result in substantial savings in time, effort, and cost for investigators in all areas of transgenic mouse research.
Subject(s)
Animals, Congenic/genetics , Genetic Markers , Animals , Female , Mice , Mice, Inbred C57BLABSTRACT
Most mixed strain progeny from gene-knockout experiments typically originate from C57BL/6J and one of the 129 substrains, frequently 129S6/SvEvTac. The results of this behavioral survey suggest that C57BL/6J:129S6/SvEvTac mixed strain mice are amenable to behavioral testing. The variability in behavioral tasks for subjects arising from this mixed strain genetic background does not preclude screening with a battery of behavioral tests. With clues provided by a screen of mixed strain subjects, follow-up analyses with isogenic, congenic, or F1 hybrid animals may be targeted to specific behavioral themes.