We study the regulation and function of adult neurogenesis in rats and mice, which show continued production of new neurons throughout adulthood similar to that in primates, including humans. During the past year, we completed a study examining the function of neurogenesis in adult mice. We made a transgenic mouse line in which we could kill neuronal precursor cells by giving the mice a drug (valganciclovir), allowing us to specifically stop neurogenesis after the mice reached adulthood. Several weeks after stopping neurogenesis, we tested the mice to look for changes due to the loss of the new neurons. In pilot studies, we noticed behaviors suggesting that the mice without neurogenesis might respond differently than controls under stressful testing conditions. To directly test this, we restrained the mice for 30 minutes, producing psychological stress without physical harm. We found that the levels of corticosterone, a glucocorticoid stress hormone, were similar in control mice and those lacking neurogenesis at the end of the stress period. However, 30 minutes after stress, corticosterone levels had recovered significantly more in control mice than in the mice without neurogenesis. Additional tests demonstrated that control and transgenic mice that were not fed the drug, and therefore had equivalent levels of neurogenesis showed no differences in stress-induced corticosterone levels, whereas mice lacking adult neurogenesis due to irradiation showed prolonged recovery of corticosterone levels, arguing that the lack of neurogenesis itself is responsible for the change in corticosterone response. Since impaired negative feedback of glucocorticoids in a dexamethasone suppression test is a common feature of depressive illness, we measured dexamethasone suppression of the stress-induced corticosterone increase and found that transgenic mice lacking adult neurogenesis showed less suppression than control mice. We then tested the behavior of the mice in three tests of depression. In the novelty-suppressed feeding test, we found no difference in the behavior of mice with and without neurogenesis under control conditions, consistent with previous findings from other groups. However, when mice were tested after acute restraint stress, the mice lacking neurogenesis showed increased latency to eat, and fewer mice ate at all during the 10 minute test, an indication of increased depressive-like behavior. In the forced swim test, which is very stressful on its own, the mice lacking neurogenesis showed enhanced immobility, also indicative of increased depressive-like behavior. Finally, in a test of reward-mediated learning, mice lacking adult neurogenesis drank less sucrose-flavored water than control mice regardless of whether they were stressed or not, suggesting anhedonia, another symptom of depression. Taken together, our findings provide the first direct evidence that new neurons in the adult hippocampus buffer against stress endocrine and behavioral stress responses and that inhibition of neurogenesis increases depressive-like behaviors.

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Project End
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Support Year
10
Fiscal Year
2011
Total Cost
$1,320,112
Indirect Cost
Name
U.S. National Institute of Mental Health
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Pothayee, Nikorn; Cummings, Diana M; Schoenfeld, Timothy J et al. (2017) Magnetic resonance imaging of odorant activity-dependent migration of neural precursor cells and olfactory bulb growth. Neuroimage 158:232-241
Schoenfeld, Timothy J; McCausland, Hayley C; Morris, H Douglas et al. (2017) Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume. Biol Psychiatry 82:914-923
Glover, Lucas R; Schoenfeld, Timothy J; Karlsson, Rose-Marie et al. (2017) Ongoing neurogenesis in the adult dentate gyrus mediates behavioral responses to ambiguous threat cues. PLoS Biol 15:e2001154
Akins, Michael R; Berk-Rauch, Hanna E; Kwan, Kenneth Y et al. (2017) Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains. Hum Mol Genet 26:192-209
Schoenfeld, Timothy J; McCausland, Hayley C; Sonti, Anup N et al. (2016) Anxiolytic Actions of Exercise in Absence of New Neurons. Hippocampus 26:1373-1378
Opendak, Maya; Offit, Lily; Monari, Patrick et al. (2016) Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis. J Neurosci 36:7027-38
Soumier, Amelie; Carter, Rayna M; Schoenfeld, Timothy J et al. (2016) New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats. eNeuro 3:
Snyder, Jason S; Grigereit, Laura; Russo, Alexandra et al. (2016) A Transgenic Rat for Specifically Inhibiting Adult Neurogenesis. eNeuro 3:
Pelkey, Kenneth A; Barksdale, Elizabeth; Craig, Michael T et al. (2015) Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron 85:1257-72
Smart, DeeDee; Garcia-Glaessner, Alejandra; Palmieri, Diane et al. (2015) Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis. Clin Exp Metastasis 32:717-27

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