Pro-neurogenic effect of fluoxetine in the olfactory bulb is concomitant to improvements in social memory and depressive-like behavior of socially isolated mice.

Although loneliness is a human experience, it can be estimated in laboratory animals deprived from physical contact with conspecifics. Rodents under social isolation (SI) tend to develop emotional distress and cognitive impairment. However, it is still to be determined whether those conditions present a common neural mechanism. Here, we conducted a series of behavioral, morphological, and neurochemical analyses in adult mice that underwent to 1 week of SI. We observed that SI mice display a depressive-like state that can be prevented by enriched environment, and the antidepressants fluoxetine (FLX) and desipramine (DES). Interestingly, chronic administration of FLX, but not DES, was able to counteract the deleterious effect of SI on social memory. We also analyzed cell proliferation, neurogenesis, and astrogenesis after the treatment with antidepressants. Our results showed that the olfactory bulb (OB) was the neurogenic niche with the highest increase in neurogenesis after the treatment with FLX. Considering that after FLX treatment social memory was rescued and depressive-like behavior decreased, we propose neurogenesis in the OB as a possible mechanism to unify the FLX ability to counteract the deleterious effect of SI.

Inhibiting constitutive neurogenesis compromises long-term social recognition memory.

Although the functional role for newborn neurons in neural circuits is still matter of investigation, there is no doubt that neurogenesis modulates learning and memory in rodents. In general, boosting neurogenesis before learning, using genetic-target tools or drugs, improves hippocampus-dependent memories. However, inhibiting neurogenesis may yield contradictory results depending on the type of memory evaluated. Here we tested the hypothesis that inhibiting constitutive neurogenesis would compromise social recognition memory (SRM). Male Swiss mice were submitted to three distinct procedures to inhibit neurogenesis: (1) intra-cerebral infusion of Cystosine-ß-D-Arabinofuranoside (AraC); (2) intra-peritoneal injection of temozolomide (TMZ) and (3) cranial gamma irradiation. All three methods decreased cell proliferation and neurogenesis in the dentate gyrus of the dorsal (dDG) and ventral hippocampus (vDG), and the olfactory bulb (OB). However, the percentage inhibition diverged between methods and brain regions. Ara-C, TMZ and gamma irradiation impaired SRM, though only gamma irradiation did not cause side effects on weight gain, locomotor activity and anxiety. Finally, we examined the contribution of cell proliferation in vDG, dDG and OB to SRM. The percent of inhibition in the dDG correlates with SRM, independently of the method utilized. This correlation was observed for granular cell layer of OB and vDG, only when the inhibition was induced by gamma irradiation. Animal's performance was restrained by the inhibition of dDG cell proliferation, suggesting that cell proliferation in the dDG has a greater contribution to SRM. Altogether, our results demonstrate that SRM, similarly to other hippocampus-dependent memories, has its formation impaired by reducing constitutive neurogenesis.

Neurogenesis Inhibition Prevents Enriched Environment to Prolong and Strengthen Social Recognition Memory, But Not to Increase BDNF Expression.

Hippocampus-dependent memories, such as social recognition (SRM), are modulated by neurogenesis. However, the precise role of newborn neurons in social memory processing is still unknown. We showed previously that 1 week of enriched environment (EE) is sufficient to increase neurogenesis in the hippocampus (HIP) and the olfactory bulb (OB) of mice. Here, we tested the hypothesis that 1 week of EE would enhance SRM persistence and strength. In addition, as brain-derived neurotrophic factor (BDNF) may mediate some of the neurogenesis effects on memory, we also tested if 1 week of EE would increase BDNF expression in the HIP and OB. We also predicted that neurogenesis inhibition would block the gain of function caused by EE on both SRM and BDNF expression. We found that EE increased BDNF expression in the HIP and OB of mice; at the same time, it allowed SRM to last longer. In addition, mice on EE had their SRM unaffected by memory consolidation interferences. As we predicted, treatment with the anti-mitotic drug AraC blocked EE effects on SRM. Surprisingly, neurogenesis inhibition did not affect the BDNF expression, increased by EE. Together, our results suggest that newborn neurons improve SRM persistence through a BDNF-independent mechanism. Interestingly, this study on social memory uncovered an unexpected dissociation between the effect of adult neurogenesis and BDNF expression on memory persistence, reassuring the idea that not all neurogenesis effects on memory are BDNF-dependent.