Olfactory neurogenesis and its role in fear memory modulation.

Olfaction is a critical sense that allows animals to navigate and understand their environment. In mammals, the critical brain structure to receive and process olfactory information is the olfactory bulb, a structure characterized by a laminated pattern with different types of neurons, some of which project to distant telencephalic structures, like the piriform cortex, the amygdala, and the hippocampal formation. Therefore, the olfactory bulb is the first structure of a complex cognitive network that relates olfaction to different types of memory, including episodic memories. The olfactory bulb continuously adds inhibitory newborn neurons throughout life; these cells locate both in the granule and glomerular layers and integrate into the olfactory circuits, inhibiting projection neurons. However, the roles of these cells modulating olfactory memories are unclear, particularly their role in fear memories. We consider that olfactory neurogenesis might modulate olfactory fear memories by a plastic process occurring in the olfactory bulb.

Hippocampal neurogenesis facilitates cognitive flexibility in a fear discrimination task.

Hippocampal neurogenesis, the continuous creation of new neurons in the adult brain, influences memory, regulates the expression of defensive responses to threat (fear), and cognitive processes like pattern separation and behavioral flexibility. One hypothesis proposes that neurogenesis promotes cognitive flexibility by degrading established memories and promoting relearning. Yet, empirical evidence on its role in fear discrimination tasks is scarce. In this study, male rats were initially trained to differentiate between two similar environments, one associated with a threat. Subsequently, we enhanced neurogenesis through environmental enrichment and memantine treatments. We then reversed the emotional valence of these contexts. In both cases, neurogenesis improved the rats' ability to relearn the aversive context. Interestingly, we observed increased hippocampal activity, and decreased activity in the prelimbic cortex and lateral habenula, while the infralimbic cortex remained unchanged, suggesting neurogenesis-induced plasticity changes in this brain network. Moreover, when we pharmacologically inhibited the increased neurogenesis with Methotrexate, rats struggled to relearn context discrimination, confirming the crucial role of neurogenesis in this cognitive process. Overall, our findings highlight neurogenesis's capacity to facilitate changes in fear discrimination and emphasize the involvement of a prefrontal-hippocampal-habenula mechanism in this process. This study emphasizes the intricate relationship between hippocampal neurogenesis, cognitive flexibility, and the modulation of fear-related memories.

Maternal enrichment increases infantile spatial amnesia mediated by postnatal neurogenesis modulation.

Infantile amnesia, the inability to form long-lasting episodic memories, is a phenomenon extensively known but with no clear understanding of its origins. However, a recent study showed that high rates of hippocampal postnatal neurogenesis degrade episodic-like memories in infants a few days after memory acquisition. Additionally, new studies indicate that exposure to an enriched environment in mice leads to high hippocampal neurogenesis in their offspring. Nevertheless, it is still unclear how this intergenerational trait affects the persistence of hippocampal memories. Therefore, we evaluated spatial memory retention in the offspring of enriched female mice after weaning to address this question. Ten days after spatial learning, we tested memory retention, observing that the offspring of enriched dams increased spatial memory failure; this finding correlates with high proliferation rates in the hippocampus. Furthermore, we evaluated the causal relationship between postnatal hippocampal neurogenesis and memory failure using the antiproliferative drug Temozolomide (TMZ), which rescued spatial memory retrieval. Finally, we evaluated neuronal activity in the hippocampus quantifying the cells expressing the immediate early gene c-Fos. This evaluation showed engram modifications between groups. This neural activity pattern indicates that the high neurogenesis rates can modify memory engrams and cognitive performance. In conclusion, the inherited increase of hippocampal neurogenesis by enriched dams leads to plastic changes that exacerbate infantile amnesia in a spatial task.

Hippocampal neurogenesis regulates recovery of defensive responses by recruiting threat- and extinction-signalling brain networks.

Safe exposure to a context that was previously associated with threat leads to extinction of defensive responses. Such contextual fear extinction involves the formation of a new memory that inhibits a previously acquired contextual fear memory. However, fear-related responses often return with the simple passage of time (spontaneous fear recovery). Given that contextual fear and extinction memories are hippocampus-dependent and hippocampal neurogenesis has been reported to modify preexisting memories, we hypothesized that neurogenesis-mediated modification of preexisting extinction memory would modify spontaneous fear recovery. To test this, rats underwent contextual fear conditioning followed by extinction. Subsequently, we exposed rats to an enriched environment or focal X-irradiation to enhance or ablate hippocampal neurogenesis, respectively. Over a month later, rats were tested to evaluate spontaneous fear recovery. We found that enhancing neurogenesis after, but not before, extinction prevented fear recovery. In contrast, neurogenesis ablation after, but not before, extinction promoted fear recovery. Using the neuronal activity marker c-Fos, we identified brain regions recruited in these opposing neurogenesis-mediated changes during fear recovery. Together, our findings indicate that neurogenesis manipulation after extinction learning modifies fear recovery by recruiting brain network activity that mediates the expression of preexisting contextual fear and extinction memories.