Molecular Psychiatry: Alcohol-dependent enzymes promote excessive storage of fearful memories

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Normal fear behavior induces adaptive responses in the body, enhances risk awareness, and avoids danger
.
Excessive fear responses cause PTSD and anxiety disorders
.
The amygdala brain region, as a key brain area for regulating fear memory and anxiety, receives input
primarily from the dorsomedial prefrontal cortex (dmPFC).

Past experiences may cause a gene "reprogramming process"
through changes in gene expression.
Epigenetic regulation is considered a key mechanism for altering transcription and translation in an empirically dependent manner
.
Histone methyltransferase PR domain 2 (PRDM2) methylates the lysine residue of histone 3 and methylates histone 3 at the lysine 9 residue (H3K9me1
).

PRDM2 downregulation is expressed down-regulated in gliomas and neuroblastomas and is associated
with increased stress response.
PRDM2 enrichment expression in dmPFC, an increase in aversion of alcohol intake after its down-regulation of expression, an increase in stress-induced recurrence of alcohol, and the promotion of alcohol addiction
.

Studies have shown that alcohol addiction behaviors and fear memory behaviors may have "shared" neurobiological mechanisms, and PRDM2 may be one of
them.

On September 21, 2022, Barbier Estelle's research team from the Department of Clinical Medicine and Biomedicine at Linköping University in Sweden revealed that the downward regulation of PRDM2 expression can enhance neuronal activity in the core brain region of fear memory, causing excessive consolidation
of fear memory.

1

PRDM2 expression downregulation promotes fear memory expression

Virus-specific knockdown of the dmPFC region after PRDM2 expression does not affect the anxiety behavior of mice, nor does it affect the acquisition of fear memory in mice, but can significantly promote the expression of fear memory, and this enhancement effect can last for one week
.

Neuron Prdm2 expression projected into the BLA (basal amygdala) region by virus-specific knockdown dmPFC does not affect the acquisition of fear memory, but promotes the expression
of fear memory.

Figure 1: PRDM2 expression down-regulation promotes fear memory expression

2

Prdm2 downregulation promotes synaptic regeneration signaling

Transcriptomic analysis of specific knockdown dmPFC projected onto neurons in the BLA region Prdm2 found that the differentially enriched expressing genes were mainly synaptic function genes (synaptic regeneration activation related genes), neurotransmitter release signaling and memory consolidation related genes
.
This suggests that Prdm2 downregulation may enhance the expression
of fearful memories by facilitating memory consolidation processes.

Figure 2: Prdm2 downregulation promotes synaptic neofunctional gene expression

3

Prdm2 downregulation increases amygdala neuronal activity

After specific knockdown of Prdm2 expression in the dmPFC region, it was found that the micro-excitatory postsynaptic current of neurons in the BLA region was enhanced, and the paired pulse ratio was reduced, which did not affect the functional expression of AMPA and NMDA glutamate receptors, which indicated that the release of glutamate by neurons in the BLA region increased
.

Fiber optic calcium imaging technology found that after knocking down Prdm2, the activity of neurons in the BLA region increased significantly after rats heard sound stimulation, which showed that the reduction of Prdm2 expression could enhance the response of BLA neurons to fear-related events
.

Figure 3: Downregulation of Prdm2 increases amygdala neuronal activity

summary

In this paper, the epigenetic modification enzyme PRDM2 is found to be used in regulating fear memory consolidation through the dmPFC-BLA neural circuit: Enhancing neuronal activity in the BLA region after reduced PRDM2 expression promotes fear memory
.

【References】

1.
Riccardo, B.
, Kanat, C.
, Michele, P.
 et al.
 An epigenetic mechanism for over-consolidation of fear memories.
 Mol Psychiatry (2022).
https://doi.
org/10.
1038/s41380-022-01758-6

The images in the article are from references