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Ventromedial hypothalamic neurons control a defensive emotion state.

Kunwar PS, Zelikowsky M, Remedios R, Cai H, Yilmaz M, Meister M, Anderson DJ - Elife (2015)

Bottom Line: The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself.Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center.These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.

ABSTRACT
Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.

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Activation of SF1+ neurons produces conditioned place avoidance learning and memory.(A) Protocol for conditioned place avoidance assay. Pre-training phase used to determine each animal's initially preferred side. (B) Representative tracking traces during pre-training, training, short-term memory (STM) and long-term memory (LTM) test phases as indicated in overlying schematic. Blue bar represents light delivery on the initially preferred side exhibited by each individual animal. (C) Percentage of total time for each phase (see panel A) spent in initially preferred side during pre-training, training (blue shading), STM test, and LTM test. Animals spontaneously spent ∼75% of their time in one of the two chambers (defined as the initially preferred side), during pre-training period. (D) Preference score (percent total time spent in the initially preferred minus the initially non-preferred side), for each experimental phase. Negative value indicates that the animal spends more time in the initially non-preferred side, than in the initially preferred side. Preference score measures distribution of animals between the two chambers during a given testing phase. (E) Preference scores from (D) replotted for comparison of pre-training vs LTM scores for ChR2-expressing (black bars) vs eYFP control mice (green bars). (F) Difference scores (percent time spent in the initially preferred side during each respective phase minus the percent time spent in the same side during the pre-training phase) for training, STM and LTM tests. Difference score measures change in time spent in initially preferred side during pre-training phase vs a given testing phase. Difference score during LTM test is ∼38% of that measured during STM test, indicating some retention of avoidance conditioning. (G) Mean velocity during each experimental phase revealed no differences. n = 7–10 animals for each condition. All values are displayed as mean ± SEM. ****p < 0.001; ***p < 0.001; **p < 0.01; *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.06633.018
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fig6: Activation of SF1+ neurons produces conditioned place avoidance learning and memory.(A) Protocol for conditioned place avoidance assay. Pre-training phase used to determine each animal's initially preferred side. (B) Representative tracking traces during pre-training, training, short-term memory (STM) and long-term memory (LTM) test phases as indicated in overlying schematic. Blue bar represents light delivery on the initially preferred side exhibited by each individual animal. (C) Percentage of total time for each phase (see panel A) spent in initially preferred side during pre-training, training (blue shading), STM test, and LTM test. Animals spontaneously spent ∼75% of their time in one of the two chambers (defined as the initially preferred side), during pre-training period. (D) Preference score (percent total time spent in the initially preferred minus the initially non-preferred side), for each experimental phase. Negative value indicates that the animal spends more time in the initially non-preferred side, than in the initially preferred side. Preference score measures distribution of animals between the two chambers during a given testing phase. (E) Preference scores from (D) replotted for comparison of pre-training vs LTM scores for ChR2-expressing (black bars) vs eYFP control mice (green bars). (F) Difference scores (percent time spent in the initially preferred side during each respective phase minus the percent time spent in the same side during the pre-training phase) for training, STM and LTM tests. Difference score measures change in time spent in initially preferred side during pre-training phase vs a given testing phase. Difference score during LTM test is ∼38% of that measured during STM test, indicating some retention of avoidance conditioning. (G) Mean velocity during each experimental phase revealed no differences. n = 7–10 animals for each condition. All values are displayed as mean ± SEM. ****p < 0.001; ***p < 0.001; **p < 0.01; *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.06633.018

Mentions: The experimental design is illustrated in Figure 6A. Before conditioning, we performed a 5 min pre-training test to determine each animal's initial chamber preference. Photostimulation during training was then carried out on each animal's initially preferred side (IPS), to determine whether training would overcome this initial preference. Training was performed over a 20-min period, using the manual closed-loop procedure described for the RTPA assays (see above). It consisted of a series of photostimulation trials lasting 10 s, or until the animal withdrew from the stimulation chamber, whichever occurred first. Trials were repeated at 10-s intervals. If the animal withdrew from the training chamber during a photostimulation trial, the next trial was administered after the animal spontaneously re-entered the stimulation chamber. Over the 20-min training period, animals that initially exhibited freezing or activity bursts in the photostimulation chamber during the first few training trials eventually responded to photostimulation during later trials by rapid withdrawal from the IPS/training chamber.10.7554/eLife.06633.018Figure 6.Activation of SF1+ neurons produces conditioned place avoidance learning and memory.


Ventromedial hypothalamic neurons control a defensive emotion state.

Kunwar PS, Zelikowsky M, Remedios R, Cai H, Yilmaz M, Meister M, Anderson DJ - Elife (2015)

Activation of SF1+ neurons produces conditioned place avoidance learning and memory.(A) Protocol for conditioned place avoidance assay. Pre-training phase used to determine each animal's initially preferred side. (B) Representative tracking traces during pre-training, training, short-term memory (STM) and long-term memory (LTM) test phases as indicated in overlying schematic. Blue bar represents light delivery on the initially preferred side exhibited by each individual animal. (C) Percentage of total time for each phase (see panel A) spent in initially preferred side during pre-training, training (blue shading), STM test, and LTM test. Animals spontaneously spent ∼75% of their time in one of the two chambers (defined as the initially preferred side), during pre-training period. (D) Preference score (percent total time spent in the initially preferred minus the initially non-preferred side), for each experimental phase. Negative value indicates that the animal spends more time in the initially non-preferred side, than in the initially preferred side. Preference score measures distribution of animals between the two chambers during a given testing phase. (E) Preference scores from (D) replotted for comparison of pre-training vs LTM scores for ChR2-expressing (black bars) vs eYFP control mice (green bars). (F) Difference scores (percent time spent in the initially preferred side during each respective phase minus the percent time spent in the same side during the pre-training phase) for training, STM and LTM tests. Difference score measures change in time spent in initially preferred side during pre-training phase vs a given testing phase. Difference score during LTM test is ∼38% of that measured during STM test, indicating some retention of avoidance conditioning. (G) Mean velocity during each experimental phase revealed no differences. n = 7–10 animals for each condition. All values are displayed as mean ± SEM. ****p < 0.001; ***p < 0.001; **p < 0.01; *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.06633.018
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fig6: Activation of SF1+ neurons produces conditioned place avoidance learning and memory.(A) Protocol for conditioned place avoidance assay. Pre-training phase used to determine each animal's initially preferred side. (B) Representative tracking traces during pre-training, training, short-term memory (STM) and long-term memory (LTM) test phases as indicated in overlying schematic. Blue bar represents light delivery on the initially preferred side exhibited by each individual animal. (C) Percentage of total time for each phase (see panel A) spent in initially preferred side during pre-training, training (blue shading), STM test, and LTM test. Animals spontaneously spent ∼75% of their time in one of the two chambers (defined as the initially preferred side), during pre-training period. (D) Preference score (percent total time spent in the initially preferred minus the initially non-preferred side), for each experimental phase. Negative value indicates that the animal spends more time in the initially non-preferred side, than in the initially preferred side. Preference score measures distribution of animals between the two chambers during a given testing phase. (E) Preference scores from (D) replotted for comparison of pre-training vs LTM scores for ChR2-expressing (black bars) vs eYFP control mice (green bars). (F) Difference scores (percent time spent in the initially preferred side during each respective phase minus the percent time spent in the same side during the pre-training phase) for training, STM and LTM tests. Difference score measures change in time spent in initially preferred side during pre-training phase vs a given testing phase. Difference score during LTM test is ∼38% of that measured during STM test, indicating some retention of avoidance conditioning. (G) Mean velocity during each experimental phase revealed no differences. n = 7–10 animals for each condition. All values are displayed as mean ± SEM. ****p < 0.001; ***p < 0.001; **p < 0.01; *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.06633.018
Mentions: The experimental design is illustrated in Figure 6A. Before conditioning, we performed a 5 min pre-training test to determine each animal's initial chamber preference. Photostimulation during training was then carried out on each animal's initially preferred side (IPS), to determine whether training would overcome this initial preference. Training was performed over a 20-min period, using the manual closed-loop procedure described for the RTPA assays (see above). It consisted of a series of photostimulation trials lasting 10 s, or until the animal withdrew from the stimulation chamber, whichever occurred first. Trials were repeated at 10-s intervals. If the animal withdrew from the training chamber during a photostimulation trial, the next trial was administered after the animal spontaneously re-entered the stimulation chamber. Over the 20-min training period, animals that initially exhibited freezing or activity bursts in the photostimulation chamber during the first few training trials eventually responded to photostimulation during later trials by rapid withdrawal from the IPS/training chamber.10.7554/eLife.06633.018Figure 6.Activation of SF1+ neurons produces conditioned place avoidance learning and memory.

Bottom Line: The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself.Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center.These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.

View Article: PubMed Central - PubMed

Affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.

ABSTRACT
Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.

Show MeSH
Related in: MedlinePlus