Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

Abstract

The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)-CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal-cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD.

The Human Dentate Gyrus Plays a Necessary Role in Discriminating New Memories

“…Hippocampal dentate gyrus/CA3 hyperactivity (and bias to pattern completion), in particular, is now being studied as a modifiable biomarker for such disorders as Alzheimer's disease and dementia (M. Yassa, personal communication, July 25, 2016). And gaining a better understanding of how the dentate gyrus/CA3 might overgeneralize episodic details relating to threat and fear might help guide the development of novel therapeutic strategies for posttraumatic stress disorder (Besnard, & Sahay, 2016;Wang et al, 2010).…”

Impact of Stress on the Brain: Pathology, Treatment and Prevention

“…Following on this, Antoine Besnard and Amar Sahay detail our up-to-date understanding of neurogenesis within the adult brain, particularly within the hippocampus, and how this process may mediate discrimination of discrete memory events. Furthermore, in stress models, this neurogenesis appears to be impaired, in part resulting in the stress-and fear-generalization that occurs with diminished hippocampal neurogenesis (Besnard and Sahay, 2016).…”

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

“…Recent neural models of fear generalization identify hippocampal substrates involved in both pattern completion (CA3 region, involved in recognizing a GS as similar to previously encountered CS+) and pattern separation (i.e., dentate gyrus, involved in recognizing a GS as dissimilar from previously encountered CS+), while subregions of the central and lateral amygdala, the bed nucleus of the stria terminalis, and the ventromedial prefrontral cortex have been implicated in expression of generalized fear (Besnard and Sahay 2015;Dunsmoor and Paz 2015;Lissek et al 2014b). It is noteworthy that models of pattern completion and separation in fear generalization are similar to hippocampus-centered models of contextual fear learning (Kheirbek et al 2012;Rudy et al 2004).…”

“…One recent review concludes that both acute and chronic SSRI administration reduce plasticity in the hippocampus and decrease expression of contextual fear learning (Burghardt and Bauer 2013), while another review suggests that chronic antidepressant administration enhances configural learning processes through promotion of neurogenesis in the dentate gyrus (Castren and Hen 2013). Given the involvement of pattern separation and pattern completion in both fear generalization and contextual fear learning, there is reason to expect that drugs promoting neurogenesis in the dentate gyrus might be used to both improve configural learning of contextual information and decrease overgeneralization of feared stimuli in PTSD patients (Besnard and Sahay 2015;Castren and Hen 2013). No research has directly examined drug modulation of contextual fear extinction in PTSD, though it has been argued that DCS promotes contextual safety learning (Vervliet 2008;Woods and Bouton 2006).…”