Gender Differences in the Neurobiology of Anxiety: Focus on Adult Hippocampal Neurogenesis

Abstract

Although the literature reports a higher incidence of anxiety disorders in women, the majority of basic research has focused on male rodents, thus resulting in a lack of knowledge on the neurobiology of anxiety in females. Bridging this gap is crucial for the design of effective translational interventions in women. One of the key brain mechanisms likely to regulate anxious behavior is adult hippocampal neurogenesis (AHN). This review paper aims to discuss the evidence on the differences between male and female rodents with regard to anxiety-related behavior and physiology, with a special focus on AHN. The differences between male and female physiologies are greatly influenced by hormonal differences. Gonadal hormones and their fluctuations during the estrous cycle have often been identified as agents responsible for sexual dimorphism in behavior and AHN. During sexual maturity, hormone levels fluctuate cyclically in females more than in males, increasing the stress response and the susceptibility to anxiety. It is therefore of great importance that future research investigates anxiety and other neurophysiological aspects in the female model, so that results can be more accurately applicable to the female population.

Figure 1

AHN is important for cognitive and emotional learning. The newly born neurons continuously generated in the postnatal hippocampus are believed to regulate cognitive and emotional tasks, as occurs in the contextual fear learning paradigm and the spatial learning assessed in the MWM. In contextual fear learning, the hippocampus is thought to be essential for the association between a previously neutral context and an aversive stimulus (in this case, a mild footshock) leading to a fear response (conditioned freezing) when the individual is reexposed to the context where the fear learning occurred. In the case of spatial learning, as assessed by the MWM, hippocampal cells are believed to play an important role in the cued spatial navigation strategies that make it possible for the rodent to more quickly find the hidden platform across the test trials. AHN = adult hippocampal neurogenesis; MWM = Morris water maze.

Box 1

Box 1: Estrous cycle.