Elevated activity in the dorsal dentate gyrus reduces expression of fear memory after fear extinction training

Abstract

Background: Effectively reducing the expression of certain aversive memories (fear or trauma memories) with extinction training is generally viewed to be therapeutically important. A deeper understanding of the biological basis for a more effective extinction process is also of high scientific importance. Methods: Our study involved intraventricular injection or local injection into the dorsal dentate gyrus of anti-neuregulin 1 antibodies (anti-NRG1) before fear extinction training, followed by testing the expression of fear memory 24 hours afterward or 9 days later. We used local injection of chemogenetic or optogenetic viruses into the dorsal dentate gyrus to manipulate the activity of the dorsal dentate gyrus and test the expression of fear memory. We also examined the effect of deep brain stimulation in the dorsal dentate gyrus on the expression of fear memory. Results: Mice that received intraventricular injection with anti-NRG1 antibodies exhibited lower expression of fear memory and increased density of activated excitatory neurons in the dorsal dentate gyrus. Injection of anti-NRG1 antibodies directly into the dorsal dentate gyrus also led to lower expression of fear memory and more activated neurons in the dorsal dentate gyrus. Inhibiting the activity of dorsal dentate gyrus excitatory neurons using an inhibitory designer receptor exclusively activated by designer drugs (DREADD) eliminated the effects of the anti-NRG1 antibodies. Enhancing the activity of the dorsal dentate gyrus with an excitatory DREADD or optogenetic stimulation resulted in lower expression of fear memory in mice that did not receive infusion of anti-NRG1 antibodies. Deep brain stimulation in the dorsal dentate gyrus effectively suppressed expression of fear memory, both during and after fear extinction training. Limitations: The mechanism for the contribution of the dorsal dentate gyrus to the expression of fear memory needs further exploration. Conclusion: Activation of the dorsal dentate gyrus may play an important role in modulating the expression of fear memory; its potential use in fear memory extinction is worthy of further exploration.

Prominent contributions of selective neuronal subtypes to pediatric drug-resistant focal dysplasia

“…To confirm that the recorded neurons is PV-positive, we performed immunofluorescence staining. 43 Slices were fixed with 4 % paraformaldehyde for 24 hr, then were dehydrated in 30% sucrose for 48 hr at 4 ℃. The sections were washed with PBS three times and 10 mins each.…”

Neurogenic Interventions for Fear Memory via Modulation of the Hippocampal Function and Neural Circuits

“…The axons of newborn neurons, known as mossy fibers, are connected to synapses with excitatory pyramidal cells in the CA3 and CA2 regions. Synaptic integration sets a time constraint on the contributions of newborn DGCs to neuronal circuitry in the adult brain [ 16 , 17 ]. Functionally mature newborn neurons are integrated into existing circuits and incorporated into the hippocampal network, which plays a critical role in long-term spatial learning and memory, pattern separation, anxiety, and fear generalization [ 18 , 19 ].…”

“…This indicates that the ACC and ventral hippocampus, via projections to the basolateral amygdala, regulate fear generalization. Zhang et al found that the chemogenetic inhibition of excitatory neuronal activity in the dorsal DG of the hippocampus is directly related to a higher expression of fear memory [ 17 ]. In contrast, enhancing neuronal activity in the dorsal DG using DREADDs (hM3D) or optogenetic stimulation reduced the percentage of freezing time, suggesting a reduced expression of fear memory.…”