Post by: Amanda McFarlan
What's the science?
Neurons that express corticotropin-releasing factor (CRF) are known to be prominent throughout the prefrontal cortex (a brain region implicated in planning complex cognitive behaviours), however, their role in cognition has yet to be elucidated. It has recently been shown that activation of CRF receptors in the caudal dorsomedial prefrontal cortex impairs spatial working memory, while inactivation of CRF receptors improves spatial working memory. This suggests that CRF may play a critical role in higher-order cognitive function. The neurobiological mechanisms by which CRF impacts working memory remain unclear. This week in the Journal of Neuroscience, Hupalo and colleagues investigated the role of CRF activity on working memory in the dorsomedial prefrontal cortex.
How did they do it?
The authors used DREADDs (designer receptors exclusively activated by designer drugs) to target the expression of either an excitatory receptor (hM3Dq) or an inhibitory receptor (hM4Di) on CRF neurons in the caudal or rostral dorsomedial prefrontal cortex in male rats. They also injected an additional group of rats with a virus lacking a DREADD transgene to serve as a control group. After recovering from surgery, the animals were trained in a working memory task where they learned to alternate between entering the left and right arms of a T-shaped maze to receive a food reward. The animals performed 20 trials per day with a delay period of 10 to 30 seconds between trials. On test day, the animals were subcutaneously injected with clozapine-N-oxide (a commonly used ligand that binds and activates DREADDs) 45 minutes before doing the working memory task to see whether it altered the activity of CRF neurons in the caudal or rostral dorsomedial prefrontal cortex. The authors compared performance levels on test day to previously established baseline performance levels to assess the effect of CRF activation on working memory. Subsequently, the authors examined whether CRF-mediated cognitive impairment acted through local and PKA-linked receptors (protein kinase A: an enzyme important for downstream cell signaling) signaling by infusing a CRF-receptor antagonist or a PKA inhibitor into the caudal dorsomedial prefrontal cortex and observing changes in performance during the working memory task. Additionally, they implanted recording electrodes in the dorsomedial prefrontal cortex to measure neuronal coding properties in response to the working memory task.
What did they find?
The authors determined that the activation of CRF neurons in the caudal, but not rostral dorsomedial prefrontal cortex significantly impaired working memory performance compared to controls. In contrast, they found that inhibiting CRF neurons in the caudal dorsomedial prefrontal cortex improved working memory performance compared to controls. These findings suggest that CRF neurons play an important role in mediating working memory performance. Further study revealed that animals expressing the excitatory DREADD receptor that were pretreated in the prefrontal cortex with a vehicle solution (which contained no drug, as a control) prior to clozapine-N-oxide (to activate the DREADD receptor) had impaired performance during the working memory task. However, this effect was completely blocked in animals pretreated with a CRF receptor antagonist or a PKA inhibitor. Together, these findings suggest that CRF neurons in the caudal dorsomedial prefrontal cortex act via PKA signaling to impair working memory.
Additionally, the authors used recording electrodes to measure neuronal activity during the working memory task. They isolated 420 wide-spiking glutamatergic (excitatory) neurons in the dorsomedial prefrontal cortex and determined that 25% of these neurons were strongly tuned to the delay interval present during the working memory task. They found that activation of CRF neurons during the working memory task (which impairs working memory) decreased the population of neurons that were strongly tuned to the delay interval by 75% compared to control groups. These findings suggest that increased activity of CRF neurons in the dorsomedial prefrontal cortex weakens the task-related coding properties of the neurons in this region.
What's the impact?
This is the first study to provide evidence that activity of CRF neurons in the caudal dorsomedial prefrontal cortex impairs working memory via PKA signaling. Additionally, activity of CRF neurons is associated with diminished task-related neuronal tuning in the caudal dorsomedial prefrontal cortex. Altogether, these findings provide insight into the frontostriatal circuitry that is important for cognition and identifies CRF as a potential target for treating cognitive dysfunction.
Hupalo et al. Prefrontal Corticotropin-Releasing Factor (CRF) Neurons Act Locally to Modulate Frontostriatal Cognition and Circuit Function. Journal of Neuroscience (2019). Access to the original scientific publication here.