Abstract
Emotional responses, such as fear and anxiety, are fundamentally important behavioral phenomena with strong fitness components in most animal species. Anxiety-related disorders continue to represent a major unmet medical need in our society, mostly because we still do not fully understand the mechanisms of these diseases. Animal models may speed up discovery of these mechanisms. The zebrafish is a highly promising model organism in this field. Here, we report the identification of a chemokine-like gene family, samdori (sam), and present functional characterization of one of its members, sam2. We show exclusive mRNA expression of sam2 in the CNS, predominantly in the dorsal habenula, telencephalon, and hypothalamus. We found knockout (KO) zebrafish to exhibit altered anxiety-related responses in the tank, scototaxis and shoaling assays, and increased crh mRNA expression in their hypothalamus compared with wild-type fish. To investigate generalizability of our findings to mammals, we developed a Sam2 KO mouse and compared it to wild-type littermates. Consistent with zebrafish findings, homozygous KO mice exhibited signs of elevated anxiety. We also found bath application of purified SAM2 protein to increase inhibitory postsynaptic transmission onto CRH neurons of the paraventricular nucleus. Finally, we identified a human homolog of SAM2, and were able to refine a candidate gene region encompassing SAM2, among 21 annotated genes, which is associated with intellectual disability and autism spectrum disorder in the 12q14.1 deletion syndrome. Taken together, these results suggest a crucial and evolutionarily conserved role of sam2 in regulating mechanisms associated with anxiety.
| Original language | English (US) |
|---|---|
| Pages (from-to) | E1041-E1050 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jan 30 2018 |
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Keywords
- Chemokine-like
- anxiety
- fear
- knockout
- zebrafish
ASJC Scopus subject areas
- General
Cite this
Targeted knockout of a chemokine-like gene increases anxiety and fear responses. / Choi, Jung Hwa; Jeong, Yun Mi; Kim, Sujin; Lee, Boyoung; Ariyasiri, Krishan; Kim, Hyun Taek; Jung, Seung Hyun; Hwang, Kyu Seok; Choi, Tae Ik; Park, Chul O.; Huh, Won Ki; Carl, Matthias; Rosenfeld, Jill A.; Raskin, Salmo; Ma, Alan; Gecz, Jozef; Kim, Hyung Goo; Kim, Jin Soo; Shin, Ho Chul; Park, Doo Sang; Gerlai, Robert; Jamieson, Bradley B.; Kim, Joon S.; Iremonger, Karl J.; Lee, Sang H.; Shin, Hee Sup; Kim, Cheol Hee.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 5, 30.01.2018, p. E1041-E1050.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeted knockout of a chemokine-like gene increases anxiety and fear responses
AU - Choi, Jung Hwa
AU - Jeong, Yun Mi
AU - Kim, Sujin
AU - Lee, Boyoung
AU - Ariyasiri, Krishan
AU - Kim, Hyun Taek
AU - Jung, Seung Hyun
AU - Hwang, Kyu Seok
AU - Choi, Tae Ik
AU - Park, Chul O.
AU - Huh, Won Ki
AU - Carl, Matthias
AU - Rosenfeld, Jill A.
AU - Raskin, Salmo
AU - Ma, Alan
AU - Gecz, Jozef
AU - Kim, Hyung Goo
AU - Kim, Jin Soo
AU - Shin, Ho Chul
AU - Park, Doo Sang
AU - Gerlai, Robert
AU - Jamieson, Bradley B.
AU - Kim, Joon S.
AU - Iremonger, Karl J.
AU - Lee, Sang H.
AU - Shin, Hee Sup
AU - Kim, Cheol Hee
PY - 2018/1/30
Y1 - 2018/1/30
N2 - Emotional responses, such as fear and anxiety, are fundamentally important behavioral phenomena with strong fitness components in most animal species. Anxiety-related disorders continue to represent a major unmet medical need in our society, mostly because we still do not fully understand the mechanisms of these diseases. Animal models may speed up discovery of these mechanisms. The zebrafish is a highly promising model organism in this field. Here, we report the identification of a chemokine-like gene family, samdori (sam), and present functional characterization of one of its members, sam2. We show exclusive mRNA expression of sam2 in the CNS, predominantly in the dorsal habenula, telencephalon, and hypothalamus. We found knockout (KO) zebrafish to exhibit altered anxiety-related responses in the tank, scototaxis and shoaling assays, and increased crh mRNA expression in their hypothalamus compared with wild-type fish. To investigate generalizability of our findings to mammals, we developed a Sam2 KO mouse and compared it to wild-type littermates. Consistent with zebrafish findings, homozygous KO mice exhibited signs of elevated anxiety. We also found bath application of purified SAM2 protein to increase inhibitory postsynaptic transmission onto CRH neurons of the paraventricular nucleus. Finally, we identified a human homolog of SAM2, and were able to refine a candidate gene region encompassing SAM2, among 21 annotated genes, which is associated with intellectual disability and autism spectrum disorder in the 12q14.1 deletion syndrome. Taken together, these results suggest a crucial and evolutionarily conserved role of sam2 in regulating mechanisms associated with anxiety.
AB - Emotional responses, such as fear and anxiety, are fundamentally important behavioral phenomena with strong fitness components in most animal species. Anxiety-related disorders continue to represent a major unmet medical need in our society, mostly because we still do not fully understand the mechanisms of these diseases. Animal models may speed up discovery of these mechanisms. The zebrafish is a highly promising model organism in this field. Here, we report the identification of a chemokine-like gene family, samdori (sam), and present functional characterization of one of its members, sam2. We show exclusive mRNA expression of sam2 in the CNS, predominantly in the dorsal habenula, telencephalon, and hypothalamus. We found knockout (KO) zebrafish to exhibit altered anxiety-related responses in the tank, scototaxis and shoaling assays, and increased crh mRNA expression in their hypothalamus compared with wild-type fish. To investigate generalizability of our findings to mammals, we developed a Sam2 KO mouse and compared it to wild-type littermates. Consistent with zebrafish findings, homozygous KO mice exhibited signs of elevated anxiety. We also found bath application of purified SAM2 protein to increase inhibitory postsynaptic transmission onto CRH neurons of the paraventricular nucleus. Finally, we identified a human homolog of SAM2, and were able to refine a candidate gene region encompassing SAM2, among 21 annotated genes, which is associated with intellectual disability and autism spectrum disorder in the 12q14.1 deletion syndrome. Taken together, these results suggest a crucial and evolutionarily conserved role of sam2 in regulating mechanisms associated with anxiety.
KW - Chemokine-like
KW - anxiety
KW - fear
KW - knockout
KW - zebrafish
UR - http://www.scopus.com/inward/record.url?scp=85041206288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041206288&partnerID=8YFLogxK
U2 - 10.1073/pnas.1707663115
DO - 10.1073/pnas.1707663115
M3 - Article
VL - 115
SP - E1041-E1050
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 5
ER -