A new “sudden fright paradigm” to explore the role of (epi)genetic modulations of the DAT gene in fear‐induced avoidance behavior

• Published in: Genes, brain and behavior Vol. 20; no. 4; pp. e12709 - n/a
• Main Authors: Zelli, Silvia, Brancato, Anna, Mattioli, Francesca, Pepe, Martina, Alleva, Enrico, Carbone, Cristiana, Cannizzaro, Carla, Adriani, Walter
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2021; John Wiley & Sons, Inc
• Subjects: Animals; Attention Deficit Disorder with Hyperactivity - genetics; Avoidance behavior; Avoidance Learning - physiology; Behavior, Animal - physiology; choice behavior; conditioned preference; DAT‐KO rats; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine transporter; Emotions - physiology; Epigenesis, Genetic - genetics; Epigenetics; Fear; Fear - physiology; fear conditioning; Gene expression; Histone deacetylase; Mental disorders; prefrontal cortex; Rats; Thalamus; dopamine transporter; fear conditioning; DAT-KO rats; conditioned preference; choice behavior; prefrontal cortex
• ISSN: 1601-1848; 1601-183X
• DOI: 10.1111/gbb.12709

Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptoms can be investigated in knock out rats for the DA transporter (DAT‐KO). Recent studies evidenced the role of epigenetic DAT modulation in depressive‐like behavior. Accordingly, we used heterozygous (HET) rats born from both HET parents (termed MIX‐HET), compared to HET rats born from WT‐mother and KO‐father (MAT‐HET), implementing the role of maternal care on DAT modulation. We developed a “sudden fright” paradigm (based on dark‐light test) to study reaction to fearful inputs in the DAT‐KO, MAT‐HET, MIX‐HET, and WT groups. Rats could freely explore the whole 3‐chambers apparatus; then, they were gently confined in one room where they experienced the fright; finally, they could freely move again. As expected, after the fearful stimulus only MAT‐HET rats showed a different behavior consisting of avoidance towards the fear‐associated chamber, compared to WT rats. Furthermore, ex‐vivo immuno‐fluorescence reveals higher prefrontal DAT levels in MAT‐HET compared to MIX‐HET and WT rats. Immuno‐fluorescence shows also a different histone deacetylase (HDAC) enzymes concentration. Since HDAC concentration could modulate gene expression, within MAT‐HET fore brain, the enhanced expression of DAT could well impair the corticostriatal‐thalamic circuit, thus causing aberrant avoidance behavior (observed only in MAT‐HET rats). DAT expression seems to be linked to a simply different breeding condition, which points to a reduced care by HET dams for epigenetic regulation. This could imply significant prefronto‐cortical influences onto the emotional processes: hence an excessively frightful response, even to mild stressful agents, may draw developmental trajectories toward anxious and depressed‐like behavior. As expected, after the fearful stimulus only MAT‐HET rats showed a different behavior consisting of avoidance towards the fear‐associated chamber, compared to WT rats. Furthermore, ex‐vivo immuno‐fluorescence reveals higher prefrontal DAT levels in MAT‐HET compared to MIX‐HET and WT rats. Immuno‐fluorescence shows alsoa different histone deacetylase enzymes concentration. Since HDAC concentration could modulate gene expression, within MAT‐HET forebrain, the enhanced expression of DAT could well impair the corticostriatal‐thalamic circuit, thus causing aberrant avoidance behavior (observed only in MAT‐HET rats). DAT expression seems to be linked to a simply different breeding condition, which points to a reduced care by HET dams for epigenetic regulation.