Part 3:Distinct Roles For The Deacetylase Domain Of HDAC3 in The Hippocampus And Medial Prefrontal Cortex in The Formation And Extinction Of Memory
Mar 15, 2022
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Acknowledgments
Special thanks to Dr. Norbert J. Fortin for his help with statistical analysis.
Funding Sources: This work was supported by the National Institute on Drug Abuse and the National Institute of Mental Health grants (DA025922, DA036984, MH101491) to MAW and NIDA and National Institute on Aging (NIA) grants (F32 DA043998 and T32 AG000096-33) to YA.
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Highlights
► Blocking HDAC3 deacetylase activity in the dorsal hippocampus enhanced long-term object location memory but had no effect on cocaine-associated memory formation. ► Impairing the HDAC3 deacetylase domain in the prelimbic cortex had no effect on cocaine-associated memory formation. ► Blocking HDAC3 deacetylase activity in the infralimbic cortex had no effect on extinction. ► Disrupting HDAC3 deacetylase activity in the dorsal hippocampus resulted in facilitated extinction.
Figure 1.
Dominant negative point mutant virus (HDAC3(Y298H)-v5 expresses effectively in the dorsal hippocampus. (A) V5 epitope was added to the point mutant virus. (B) Representative immunofluorescence image showing expression of the V5 epitope tag (green) in the dorsal hippocampus (DH) after infusion of AAV-HDAC3(Y298H)-v5. No V5 staining was observed with the AAV-EV control virus. Cells were counterstained with DAPI (blue). (C) V5 mRNA was significantly increased in the DH ofmice infused with AAV- HDAC3(Y298H)-v5, AAV-EV n = 5, HDAC3(Y298H)-v5 n = 4. (D) HDAC3 was also significantly increased in the DH ofmice infused with AAV-HDAC(Y298H)-v5 compared to AAV-EV controls, AV-EV n = 6, HDAC3(Y298H)-v5 n = 6. *p < 0.05.
Figure 2.
Blocking HDAC3 activity in the DH enhanced memory for object location (OLM), but not for object recognition (ORM). (A) Mice received subthreshold training (3 min) in an environment with two identical objects and received a retention test 24 hours later in which one object is moved to a new location. Schematic describes methods for B and C. (B) Mice given AAV-HDAC3(Y298H)-v5 showed a significant preference for the novel object location 24h after training compared with EV controls, AAV-EV n = 8, HDAC3(Y298H)-v5 n = 6. (C) Groups did not differ in total exploration time ofthe two objects. (D) Mice received subthreshold training (3 min) in an environment with two identical objects and received a retention test 24 hours later in which one object was replaced with a novel one (ORM), AAV-EV n = 9, HDAC3(Y298H)-v5 n = 7. Schematic describes methods for E and F. (E) Neither AAV-EV control or AAV-HDAC3(Y298H)-v5 mice exhibited significant preference for the novel object. (F) Groups did not differ in total exploration time ofthe two objects. *p < 0.05.
Figure 3.
Blocking HDAC3 activity in the dorsal hippocampus has no effect on the formation of cocaine-induced CPP memory. (A) Schematic ofthe cocaine-CPP procedure. (B) Cocaine- CPP expression indicated by mean CPP score (time spent in cocaine-paired (CS+) minus saline-paired (CS−) ± s.e.m). At 5 mg/kg cocaine conditioning dose, AAV-HDAC3(Y298H)- v5 mice exhibited similar CPP score to EV controls during the post-test, AAV-EV n = 15, HDAC3(Y298H)-v5 n = 15.
Figure 4.
Focal homozygous gene deletion ofHdac3 in the dorsal hippocampus has no effect on the formation of cocaine-induced CPP memory. (A) Schematic ofthe cocaine-CPP procedure. (B) Cocaine-CPP expression indicated by mean CPP score (time spent in cocaine-paired (CS +) minus saline-paired (CS−) ± s.e.m). At 5 mg/kg cocaine conditioning dose, Hdac3flox/flox mice exhibited similar CPP score to Hdac3+/+ controls during the post-test. (C) Representative immunofluorescence image showing expression ofHDAC3 (green) in the dorsal hippocampus after infusion ofAAV2.1 Cre infused in Hdac3+/+ and Hdac3flox/flox mice. Cells were counterstained with DAPI (blue). (D) Quantification of immunostaining confirmed that HDAC3 was significantly reduced in Hdac3flox/flox mice compared to Hdac3+/+ controls, Hdac3+/+ n = 12, Hdac3flox/flox n = 11. *p < 0.05.
Figure 5.
Blocking HDAC3 activity in the prelimbic cortex (PrL) has no effect on the formation of cocaine-induced CPP memory. (A) Schematic ofthe cocaine-CPP procedure. (B) Cocaine- CPP expression indicated by mean CPP score (time spent in cocaine-paired (CS+) minus saline-paired (CS−) ± s.e.m). At 5 mg/kg cocaine conditioning dose, AAV-HDAC3(Y298H)- v5 mice exhibited similar CPP score to EV controls during the post-test, AAV-EV n = 12, HDAC3(Y298H)-v5 n = 12. (C) Representative immunofluorescence image showing expression of the V5 epitope tag (green) after infusion of AAV-HDAC3(Y298H)-v5 targeting the PrL. No V5 staining was observed with the AAV-EV control virus. Cells were counterstained with DAPI (blue) and neurons were counterstained with NeuroTrace (red). V5 expression was largely confined to the prelimbic region of the medial prefrontal cortex. (D) Targeted viral infusion in the PrL. The shaded regions ofthe mouse atlas images illustrate the representative extend of viral infusion.
Figure 6.
Blocking HDAC3 activity in the infralimbic cortex (IL) has no effect on the extinction of cocaine-induced CPP memory. (A) Schematic of the cocaine-CPP procedure. (B) Cocaine- CPP expression indicated by mean CPP score (time spent in cocaine-paired (CS+) minus saline-paired (CS−) ± s.e.m). Animals were initially trained on 20 mg/kg of cocaine. Subsequently, animals received intra-IL AAV-EV or AAV-HDAC3(Y298H)-v5 viral infusions, and extinction memory was examined. AAV-HDAC3(Y298H)-v5 mice exhibited similar CPP score to EV controls during post-tests 2–5, AAV-EV n = 17, HDAC3(Y298H)- v5 n = 16. (C) Representative immunofluorescence image showing expression of the V5 epitope tag (green) after infusion of AAV-HDAC3(Y298H)-v5 targeting the IL. No V5 staining was observed with the AAV-EV control virus. Cells were counterstained with DAPI (blue) and neurons were counterstained with NeuroTrace (red). V5 expression was largely confined to the infralimbic region of the medial prefrontal cortex. (D) Targeted viral infusion in the IL. The shaded regions of the mouse atlas images illustrate the representative extent of viral infusion.
