PMID- 33160605
OWN - NLM
STAT- MEDLINE
DCOM- 20210423
LR  - 20220531
IS  - 1873-2402 (Electronic)
IS  - 0006-3223 (Linking)
VI  - 89
IP  - 4
DP  - 2021 Feb 15
TI  - Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives 
      Alcohol-Associated Behaviors in Rats.
PG  - 398-406
LID - S0006-3223(20)31886-2 [pii]
LID - 10.1016/j.biopsych.2020.08.027 [doi]
AB  - BACKGROUND: Alcohol addiction is characterized by persistent neuroadaptations in 
      brain structures involved in motivation, emotion, and decision making, including 
      the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We 
      previously reported that induction of alcohol dependence was associated with 
      long-term changes in the expression of genes involved in neurotransmitter 
      release. Specifically, Syt1, which plays a key role in neurotransmitter release 
      and neuronal functions, was downregulated. Here, we therefore examined the role 
      of Syt1 in alcohol-associated behaviors in rats. METHODS: We evaluated the effect 
      of Syt1 downregulation using an adeno-associated virus (AAV) containing a short 
      hairpin RNA against Syt1. Cre-dependent Syt1 was also used in combination with an 
      rAAV2 retro-Cre virus to assess circuit-specific effects of Syt1 knockdown (KD). 
      RESULTS: Alcohol-induced downregulation of Syt1 is specific to the prelimbic 
      cortex (PL), and KD of Syt1 in the PL resulted in escalated alcohol consumption, 
      increased motivation to consume alcohol, and increased alcohol drinking despite 
      negative consequences ("compulsivity"). Syt1 KD in the PL altered the 
      excitation/inhibition balance in the basolateral amygdala, while the nucleus 
      accumbens core was unaffected. Accordingly, a projection-specific Syt1 KD in the 
      PL-basolateral amygdala projection was sufficient to increase compulsive alcohol 
      drinking, while a KD of Syt1 restricted to PL-nucleus accumbens core projecting 
      neurons had no effect on tested alcohol-related behaviors. CONCLUSIONS: Together, 
      these data suggest that dysregulation of Syt1 is an important mechanism in 
      long-term neuroadaptations observed after a history of alcohol dependence, and 
      that Syt1 regulates alcohol-related behaviors in part by affecting a 
      PL-basolateral amygdala brain circuit.
CI  - Copyright (c) 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All 
      rights reserved.
FAU - Barbier, Estelle
AU  - Barbier E
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden. Electronic address: 
      estelle.barbier@liu.se.
FAU - Barchiesi, Riccardo
AU  - Barchiesi R
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden.
FAU - Domi, Ana
AU  - Domi A
AD  - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of 
      Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 
      Gothenburg, Sweden.
FAU - Chanthongdee, Kanat
AU  - Chanthongdee K
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden; Department of 
      Physiology, Faculty of Medicine Siraj Hospital, Mahidol University, Bangkok, 
      Thailand.
FAU - Domi, Esi
AU  - Domi E
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden.
FAU - Augier, Gaelle
AU  - Augier G
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden.
FAU - Augier, Eric
AU  - Augier E
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden.
FAU - Xu, Li
AU  - Xu L
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden; Psychosomatic 
      Medicine Center, Sichuan Academy of Medical Sciences, Sichuan Provincial People's 
      Hospital, Chengdu, China.
FAU - Adermark, Louise
AU  - Adermark L
AD  - Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of 
      Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 
      Gothenburg, Sweden.
FAU - Heilig, Markus
AU  - Heilig M
AD  - Center for Social and Affective Neuroscience, Department of Biomedical and 
      Clinical Sciences, Linkoping University, Linkoping, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200908
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 (Synaptotagmin I)
RN  - 0 (Syt1 protein, rat)
RN  - 3K9958V90M (Ethanol)
SB  - IM
MH  - Amygdala
MH  - Animals
MH  - Down-Regulation
MH  - Ethanol
MH  - Nucleus Accumbens
MH  - *Prefrontal Cortex
MH  - Rats
MH  - *Synaptotagmin I/genetics
OTO - NOTNLM
OT  - Alcohol addiction
OT  - Basolateral amygdala
OT  - Compulsivity
OT  - Nucleus accumbens
OT  - Prelimbic cortex
OT  - Syt1
EDAT- 2020/11/09 06:00
MHDA- 2021/04/24 06:00
CRDT- 2020/11/08 20:24
PHST- 2020/05/15 00:00 [received]
PHST- 2020/08/17 00:00 [revised]
PHST- 2020/08/25 00:00 [accepted]
PHST- 2020/11/09 06:00 [pubmed]
PHST- 2021/04/24 06:00 [medline]
PHST- 2020/11/08 20:24 [entrez]
AID - S0006-3223(20)31886-2 [pii]
AID - 10.1016/j.biopsych.2020.08.027 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2021 Feb 15;89(4):398-406. doi: 10.1016/j.biopsych.2020.08.027. 
      Epub 2020 Sep 8.