Hippocampal neurogenesis decreases PTSD symptoms in mice, study finds

A study on mice found that interventions increasing the creation of new neurons in the hippocampus (hippocampal neurogenesis) weaken memories of traumatic events and reduce PTSD symptoms. The research was published in Molecular Psychiatry.

Early researchers of brain development believed that the brain stops creating new neurons once a person reaches adulthood. However, newer studies indicate that even adult brains continue to produce new neurons, particularly in the hippocampus. This process is referred to as hippocampal neurogenesis.

Estimates suggest that 700 new neurons are generated daily in each hemisphere, amounting to an annual turnover of 1.75% of neurons. However, the survival and possibly the generation rate of these neurons depend on their incorporation into brain circuits. Studies indicate that new neurons die off if they are not integrated into brain circuits by the time they are one week old.

The hippocampus plays a critical role in the formation, organization, and retrieval of long-term memories. Integration of new neurons into neural circuits in this region may aid in forming new memories but could also facilitate forgetting existing memories through remodeling neural circuits.

Study author Risako Fujikawa and colleagues explored whether promoting forgetting by stimulating the hippocampus to produce new neurons could help in forgetting maladaptive memories associated with conditions like posttraumatic stress disorder (PTSD). PTSD is a psychiatric disorder that can occur in individuals who have experienced or witnessed traumatic events.

The researchers conducted a study on mice aged 8–12 weeks at the start of the experiments. The mice were housed in cages with 2–5 mice per cage and had free access to food and water. PTSD-like symptoms were induced in these mice using a combination of two traumatic events.

The first event involved delivering a high-intensity foot shock in a specially designed box. A mouse was placed in the “safe” part of the box, and after 10 seconds, the door to a second compartment was opened. One second after the mouse entered the second compartment, the door was closed, and a two-second electric shock was delivered to its feet. Following the shock, the mouse remained in the compartment for 10 seconds before being returned to its home cage. To induce PTSD-like symptoms, the mice received a second treatment, referred to as a “reminder shock,” in a new box. This procedure is known as the double trauma PTSD paradigm.

To assess the severity of PTSD-like symptoms, the researchers used behavioral tests, including open-field exploration and conditioned place preference. They then conducted experiments aimed at stimulating hippocampal neurogenesis through genetic manipulation, optogenetics, and exercise using running wheels. Afterward, the researchers analyzed the mice’s brain tissues.

The results showed that the double trauma paradigm produced lasting behavioral effects. Mice with access to running wheels for 30 days exhibited fewer PTSD-like behaviors than sedentary mice. Further analysis revealed that exercise led to a threefold increase in the number of new neurons in the hippocampus.

Additional experiments involved genetic manipulation to induce hippocampal neurogenesis and promote the integration of new neurons into neural circuits. These interventions weakened trauma memories (evidenced by reduced recall of features associated with shock locations) and decreased PTSD-like symptoms in the mice.

“We showed that elevating hippocampal neurogenesis [generation of new neurons in the hippocampus] attenuated PTSD-related behavioral phenotypes [behaviors] in mice. In this paradigm, consecutive traumatic experiences lead to a constellation of behavioral phenotypes associated with PTSD including deficient extinction, threat generalization and anxiety-like behavior,” the study authors concluded.

“Elevation of hippocampal neurogenesis weakened the original trauma memory, and blunted the associated deficient extinction, threat generalization, and anxiety-like phenotypes [PTSD-like behaviors]. These beneficial effects were observed using a range of interventions to manipulate hippocampal neurogenesis, including voluntary exercise and more neurogenesis-specific interventions that promote hyper-integration of new neurons into hippocampal circuits.”

The study sheds light on a neural mechanism that could potentially be leveraged to alleviate PTSD symptoms in humans. However, it is important to note that the research was conducted on mice, not humans. While mice and humans share many physiological similarities, they are distinct species, and the findings may not directly translate to humans.

The paper, “Neurogenesis-dependent remodeling of hippocampal circuits reduces PTSD-like behaviors in adult mice,” was authored by Risako Fujikawa, Adam I. Ramsaran, Axel Guskjolen, Juan de la Parra, Yi Zou, Andrew J. Mocle, Sheena A. Josselyn, and Paul W. Frankland.