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ASIC1A in the bed nucleus of the stria terminalis mediates TMT-evoked freezing.

Taugher RJ, Ghobbeh A, Sowers LP, Fan R, Wemmie JA - Front Neurosci (2015)

Bottom Line: Consistent with this possibility, olfactory bulb lesions attenuated this effect of TMT, as well as freezing.However, unlike TMT, butyric acid did not induce freezing.We found region-restricted expression of ASIC1A in the BNST increased TMT-elicited freezing.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Iowa Iowa City, IA, USA ; Department of Veterans Affairs Medical Center Iowa City, IA, USA.

ABSTRACT
Mice display an unconditioned freezing response to TMT, a predator odor isolated from fox feces. Here we found that in addition to freezing, TMT caused mice to decrease breathing rate, perhaps because of the aversive smell. Consistent with this possibility, olfactory bulb lesions attenuated this effect of TMT, as well as freezing. Interestingly, butyric acid, another foul odor, also caused mice to reduce breathing rate. However, unlike TMT, butyric acid did not induce freezing. Thus, although these aversive odors may affect breathing, the unpleasant smell and suppression of breathing by themselves are insufficient to cause freezing. Because the acid-sensing ion channel-1A (ASIC1A) has been previously implicated in TMT-evoked freezing, we tested whether Asic1a disruption also altered breathing. We found that TMT reduced breathing rate in both Asic1a(+/+) and Asic1a(-/-) mice, suggesting that ASIC1A is not required for TMT to inhibit breathing and that the absence of TMT-evoked freezing in the Asic1a(-/-) mice is not due to an inability to detect TMT. These observations further indicate that ASIC1A must affect TMT freezing in another way. Because the bed nucleus of the stria terminalis (BNST) has been critically implicated in TMT-evoked freezing and robustly expresses ASIC1A, we tested whether ASIC1A in the BNST plays a role in TMT-evoked freezing. We disrupted ASIC1A in the BNST of Asic1a(loxP/loxP) mice by delivering Cre recombinase to the BNST with an adeno-associated virus (AAV) vector. We found that disrupting ASIC1A in the BNST reduced TMT-evoked freezing relative to control mice in which a virus expressing eGFP was injected. To test whether ASIC1A in the BNST was sufficient to increase TMT-evoked freezing, we used another AAV vector to express ASIC1A in the BNST of Asic1a(-/-) mice. We found region-restricted expression of ASIC1A in the BNST increased TMT-elicited freezing. Together, these data suggest that the BNST is a key site of ASIC1A action in TMT-evoked freezing.

No MeSH data available.


Related in: MedlinePlus

ASIC1A in the BNST is necessary for normal TMT-evoked freezing. (A,B) Examples of ASIC1A immunohistochemistry in the BNST of Asic1aloxP/loxP mice injected with AAV-eGFP or AAV-Cre, showing a decrease in ASIC1A expression in the BNST (arrow) in the AAV-Cre injected mouse. (C) Cre-mediated disruption of Asic1a in the BNST reduced TMT-evoked freezing [t(30) = 2.643, *p = 0.0129, AAV-eGFP n = 19, AAV-Cre n = 13].
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Figure 3: ASIC1A in the BNST is necessary for normal TMT-evoked freezing. (A,B) Examples of ASIC1A immunohistochemistry in the BNST of Asic1aloxP/loxP mice injected with AAV-eGFP or AAV-Cre, showing a decrease in ASIC1A expression in the BNST (arrow) in the AAV-Cre injected mouse. (C) Cre-mediated disruption of Asic1a in the BNST reduced TMT-evoked freezing [t(30) = 2.643, *p = 0.0129, AAV-eGFP n = 19, AAV-Cre n = 13].

Mentions: ASIC1A is relatively abundant in many of the fear circuit structures that have been previously implicated in TMT-evoked freezing, including the BNST, PAG, and medial and basolateral amygdala (Wemmie et al., 2003; Coryell et al., 2007; Price et al., 2014). Because the BNST has been critically implicated in TMT-evoked freezing (Fendt et al., 2003), and because the BNST is a key site of ASIC1A action in freezing to another unconditioned stimulus, CO2 (Taugher et al., 2014), we hypothesized that the BNST might be a key site of ASIC1A action in TMT-evoked freezing. To test this hypothesis, we used AAV-Cre to selectively disrupt ASIC1A in the BNST of Asic1aloxP/loxP mice. Consistent with our previous observations (Taugher et al., 2014), injection of AAV-Cre into the BNST of Asic1aloxP/loxP mice effectively reduced ASIC1A expression the BNST, including both dorsal and ventral portions of the BNST and potentially in closely adjacent structures (Figures 3A,B). Next, we tested the behavioral effects of this manipulation on TMT-evoked freezing behavior. Disruption of ASIC1A in the BNST significantly reduced TMT-evoked freezing (Figure 3C), suggesting that the BNST is a key site of ASIC1A action in TMT-evoked freezing.


ASIC1A in the bed nucleus of the stria terminalis mediates TMT-evoked freezing.

Taugher RJ, Ghobbeh A, Sowers LP, Fan R, Wemmie JA - Front Neurosci (2015)

ASIC1A in the BNST is necessary for normal TMT-evoked freezing. (A,B) Examples of ASIC1A immunohistochemistry in the BNST of Asic1aloxP/loxP mice injected with AAV-eGFP or AAV-Cre, showing a decrease in ASIC1A expression in the BNST (arrow) in the AAV-Cre injected mouse. (C) Cre-mediated disruption of Asic1a in the BNST reduced TMT-evoked freezing [t(30) = 2.643, *p = 0.0129, AAV-eGFP n = 19, AAV-Cre n = 13].
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4508508&req=5

Figure 3: ASIC1A in the BNST is necessary for normal TMT-evoked freezing. (A,B) Examples of ASIC1A immunohistochemistry in the BNST of Asic1aloxP/loxP mice injected with AAV-eGFP or AAV-Cre, showing a decrease in ASIC1A expression in the BNST (arrow) in the AAV-Cre injected mouse. (C) Cre-mediated disruption of Asic1a in the BNST reduced TMT-evoked freezing [t(30) = 2.643, *p = 0.0129, AAV-eGFP n = 19, AAV-Cre n = 13].
Mentions: ASIC1A is relatively abundant in many of the fear circuit structures that have been previously implicated in TMT-evoked freezing, including the BNST, PAG, and medial and basolateral amygdala (Wemmie et al., 2003; Coryell et al., 2007; Price et al., 2014). Because the BNST has been critically implicated in TMT-evoked freezing (Fendt et al., 2003), and because the BNST is a key site of ASIC1A action in freezing to another unconditioned stimulus, CO2 (Taugher et al., 2014), we hypothesized that the BNST might be a key site of ASIC1A action in TMT-evoked freezing. To test this hypothesis, we used AAV-Cre to selectively disrupt ASIC1A in the BNST of Asic1aloxP/loxP mice. Consistent with our previous observations (Taugher et al., 2014), injection of AAV-Cre into the BNST of Asic1aloxP/loxP mice effectively reduced ASIC1A expression the BNST, including both dorsal and ventral portions of the BNST and potentially in closely adjacent structures (Figures 3A,B). Next, we tested the behavioral effects of this manipulation on TMT-evoked freezing behavior. Disruption of ASIC1A in the BNST significantly reduced TMT-evoked freezing (Figure 3C), suggesting that the BNST is a key site of ASIC1A action in TMT-evoked freezing.

Bottom Line: Consistent with this possibility, olfactory bulb lesions attenuated this effect of TMT, as well as freezing.However, unlike TMT, butyric acid did not induce freezing.We found region-restricted expression of ASIC1A in the BNST increased TMT-elicited freezing.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, University of Iowa Iowa City, IA, USA ; Department of Veterans Affairs Medical Center Iowa City, IA, USA.

ABSTRACT
Mice display an unconditioned freezing response to TMT, a predator odor isolated from fox feces. Here we found that in addition to freezing, TMT caused mice to decrease breathing rate, perhaps because of the aversive smell. Consistent with this possibility, olfactory bulb lesions attenuated this effect of TMT, as well as freezing. Interestingly, butyric acid, another foul odor, also caused mice to reduce breathing rate. However, unlike TMT, butyric acid did not induce freezing. Thus, although these aversive odors may affect breathing, the unpleasant smell and suppression of breathing by themselves are insufficient to cause freezing. Because the acid-sensing ion channel-1A (ASIC1A) has been previously implicated in TMT-evoked freezing, we tested whether Asic1a disruption also altered breathing. We found that TMT reduced breathing rate in both Asic1a(+/+) and Asic1a(-/-) mice, suggesting that ASIC1A is not required for TMT to inhibit breathing and that the absence of TMT-evoked freezing in the Asic1a(-/-) mice is not due to an inability to detect TMT. These observations further indicate that ASIC1A must affect TMT freezing in another way. Because the bed nucleus of the stria terminalis (BNST) has been critically implicated in TMT-evoked freezing and robustly expresses ASIC1A, we tested whether ASIC1A in the BNST plays a role in TMT-evoked freezing. We disrupted ASIC1A in the BNST of Asic1a(loxP/loxP) mice by delivering Cre recombinase to the BNST with an adeno-associated virus (AAV) vector. We found that disrupting ASIC1A in the BNST reduced TMT-evoked freezing relative to control mice in which a virus expressing eGFP was injected. To test whether ASIC1A in the BNST was sufficient to increase TMT-evoked freezing, we used another AAV vector to express ASIC1A in the BNST of Asic1a(-/-) mice. We found region-restricted expression of ASIC1A in the BNST increased TMT-elicited freezing. Together, these data suggest that the BNST is a key site of ASIC1A action in TMT-evoked freezing.

No MeSH data available.


Related in: MedlinePlus