Hypothalamic Oxytocin Neurons Represent Fear Engrams in Rats

Post by Lincoln Tracy

What's the science?

Emotional memory representations or engrams (i.e. memory traces, stored in the brain) such as fear, are critical for survival. These engrams allow both animals and humans to sense, evaluate, and respond to dangerous situations in an appropriate manner. Two brain regions involved in the development of fear-related memories—the hypothalamus and the central nucleus of the amygdala (CeA)—are connected by oxytocin neurons. The endogenous hormone oxytocin may play an important role in modulating fear, due to its ability to modulate the salience of social cues and events. However, the exact role of hypothalamic oxytocin neurons in fear conditioning or learning is unknown. This week in Neuron, Hasan and colleagues developed a novel genetic tagging method—virus-delivered genetic activity-induced tagging of cell ensembles, or vGATE—to tag fear-activated oxytocin neurons in rat brains during fear conditioning.

How did they do it?

First, the authors developed the novel genetic method vGATE in a small subset of hypothalamic oxytocin neurons. This method uses a c-fos promoter and three different viruses to identify and permanently tag a small subset of neurons with fluorescent proteins. After confirming that their model worked, they investigated what proportion of the hypothalamic oxytocin neurons contributed to the anxiolytic effect and how these neurons were recruited during fear using a fear conditioning paradigm. They then analyzed brain slices to determine whether the hypothalamic oxytocin neurons projected to the CeA. The authors also used optogenetics—a technique in which neural activity can be controlled by shining light on the vGATE neurons—to investigate whether fear-related behaviors could be controlled. They used histology and electrophysiology to investigate potential anatomical and molecular changes in the brain following fear experience. Finally, they introduced a novel context to the fear conditioning paradigm to investigate the role of hypothalamic oxytocin neurons in fear extinction.

What did they find?

First, the authors found that only a small proportion of the hypothalamic oxytocin neurons—approximately 13 percent—were active during the expression of fear. Second, they found that the majority of vGATE hypothalamic oxytocin neurons projected to the lateral part of the CeA. Third, when the vGATE oxytocin neurons were optogenetically simulated with a blue light there was a substantial reduction in the amount of time the rats were frozen with fear. Fourth, they found that the vGATE oxytocin neurons showed increased glutamatergic—but not oxytocinergic—transmission within the medial CeA during fear exposure. Finally, they found that inhibiting the vGATE oxytocin neurons exclusively impaired fear extinction, suggesting that fear extinction involves blocking oxytocin and glutamate mediated neural modulation in the CeA. These findings suggest that the vGATE oxytocin neurons represent a neuromodulatory memory trace that is a vital contributor to controlling fear-related memories and behaviors.    

What's the impact?

This study is the first to demonstrate that vGATE-assisted hypothalamic oxytocin neurons are adequate to drive fear-related behaviors and are required for extinction of these behaviors. Importantly, experiencing fear leads to large amounts of neural plasticity, bringing about a shift in the lateral CeA from oxytocin signaling to glutamate signaling. These findings have important implications for future investigations of the pathophysiological mechanisms that underlie emotion-based mental disorders (such as PTSD) and their potential treatments, including exogenously administered oxytocin and virus-delivered genetically based therapies.

Hasan et al. A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin System. Neuron (2019). Access the original scientific publication here.