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Trace Eyeblink Conditioning in Mice Is Dependent upon the Dorsal Medial Prefrontal Cortex, Cerebellum, and Amygdala: Behavioral Characterization and Functional Circuitry(1,2,3).

Siegel JJ, Taylor W, Gray R, Kalmbach B, Zemelman BV, Desai NS, Johnston D, Chitwood RA - eNeuro (2015)

Bottom Line: To identify the circuitry involved, we made restricted lesions of the medial prefrontal cortex (mPFC) and found that learning was prevented.Anatomical data from these critical regions showed that mPFC and amygdala both project to the rostral basilar pons and overlap with eyelid-associated pontocerebellar neurons.The data further reveal a specific role for the amygdala as providing a conditioned stimulus-associated input to the cerebellum.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Learning and Memory, University of Texas at Austin , Austin, Texas 78712.

ABSTRACT
Trace eyeblink conditioning is useful for studying the interaction of multiple brain areas in learning and memory. The goal of the current work was to determine whether trace eyeblink conditioning could be established in a mouse model in the absence of elicited startle responses and the brain circuitry that supports this learning. We show here that mice can acquire trace conditioned responses (tCRs) devoid of startle while head-restrained and permitted to freely run on a wheel. Most mice (75%) could learn with a trace interval of 250 ms. Because tCRs were not contaminated with startle-associated components, we were able to document the development and timing of tCRs in mice, as well as their long-term retention (at 7 and 14 d) and flexible expression (extinction and reacquisition). To identify the circuitry involved, we made restricted lesions of the medial prefrontal cortex (mPFC) and found that learning was prevented. Furthermore, inactivation of the cerebellum with muscimol completely abolished tCRs, demonstrating that learned responses were driven by the cerebellum. Finally, inactivation of the mPFC and amygdala in trained animals nearly abolished tCRs. Anatomical data from these critical regions showed that mPFC and amygdala both project to the rostral basilar pons and overlap with eyelid-associated pontocerebellar neurons. The data provide the first report of trace eyeblink conditioning in mice in which tCRs were driven by the cerebellum and required a localized region of mPFC for acquisition. The data further reveal a specific role for the amygdala as providing a conditioned stimulus-associated input to the cerebellum.

No MeSH data available.


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Trace 50-250 CRs were amygdala-dependent in mice, with no residual CR components. A, Bilateral infusions of muscimol (1mm, 100–150 nl) were used to inactivate the anterior central nuclei of the amygdala in 6 trained mice (left). The expression of CRs were nearly abolished (2–9% CR rates) during infusion sessions in all 6 mice (right graph, red markers; paired t = 14.27, df = 5, p < 0.001), whereas the CR rates observed during control infusions were not different than preinfusion sessions (cyan markers; t = 2.34, p = 0.07). B, Example behavior from muscimol (denoted by red text) and control sessions (cyan text) for two mice. Note the significant decrease in the expression of CRs during muscimol infusion sessions, while behavior during control sessions was less globally affected by the infusion procedure. Br, Bregma; CeA, central nucleus of the amygdala; BLA and BMA, basolateral and basomedial nuclei of the amygdala, respectively; CPu, caudate putamen; GP, globus pallidus; ic, internal capsule.
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Figure 9: Trace 50-250 CRs were amygdala-dependent in mice, with no residual CR components. A, Bilateral infusions of muscimol (1mm, 100–150 nl) were used to inactivate the anterior central nuclei of the amygdala in 6 trained mice (left). The expression of CRs were nearly abolished (2–9% CR rates) during infusion sessions in all 6 mice (right graph, red markers; paired t = 14.27, df = 5, p < 0.001), whereas the CR rates observed during control infusions were not different than preinfusion sessions (cyan markers; t = 2.34, p = 0.07). B, Example behavior from muscimol (denoted by red text) and control sessions (cyan text) for two mice. Note the significant decrease in the expression of CRs during muscimol infusion sessions, while behavior during control sessions was less globally affected by the infusion procedure. Br, Bregma; CeA, central nucleus of the amygdala; BLA and BMA, basolateral and basomedial nuclei of the amygdala, respectively; CPu, caudate putamen; GP, globus pallidus; ic, internal capsule.

Mentions: In addition to sometimes driving a noncerebellar learned eyelid response (see Introduction), it has also been suggested that the amygdala may facilitate other inputs to the pons and enhance the neural representation of the CS before being projected to the cerebellum. As a follow-up to the cerebellar inactivation experiment, we tested the amygdala-dependence of learned responses for trace 50–250 by infusing muscimol into the central nucleus after training to asymptotic performance (6/7 implanted mice learned, preinfusion mean = 70 ± 5% CR rate). Inactivation resulted in significant decreases in the expression of CRs in all six mice (infusion session mean = 5 ± 1% CR rate, paired t = 14.27, df = 5, p < 0.001y; Fig. 9A, right, example behavioral sessions given in B, left). Control infusions did not reliably affect the expression of CRs using the same procedures (precontrol infusion mean = 77 ± 5% CR rate, control infusion mean = 59 ± 8% CR rate; paired t = 2.34, df = 5, p = 0.07z; Fig. 9A, right; examples given in B, right). Because the CRs in our trained mice are dominated by a well timed response that is reminiscent of the previously reported cerebellar component (Koekkoek et al., 2005; Sakamoto and Endo, 2010), and given the known hodology, we interpret these results as suggesting that the amygdala, like the mPFC and primary sensory regions, may provide a CS-associated input to the cerebellum that supports the learning and ongoing cerebellar expression of CRs.


Trace Eyeblink Conditioning in Mice Is Dependent upon the Dorsal Medial Prefrontal Cortex, Cerebellum, and Amygdala: Behavioral Characterization and Functional Circuitry(1,2,3).

Siegel JJ, Taylor W, Gray R, Kalmbach B, Zemelman BV, Desai NS, Johnston D, Chitwood RA - eNeuro (2015)

Trace 50-250 CRs were amygdala-dependent in mice, with no residual CR components. A, Bilateral infusions of muscimol (1mm, 100–150 nl) were used to inactivate the anterior central nuclei of the amygdala in 6 trained mice (left). The expression of CRs were nearly abolished (2–9% CR rates) during infusion sessions in all 6 mice (right graph, red markers; paired t = 14.27, df = 5, p < 0.001), whereas the CR rates observed during control infusions were not different than preinfusion sessions (cyan markers; t = 2.34, p = 0.07). B, Example behavior from muscimol (denoted by red text) and control sessions (cyan text) for two mice. Note the significant decrease in the expression of CRs during muscimol infusion sessions, while behavior during control sessions was less globally affected by the infusion procedure. Br, Bregma; CeA, central nucleus of the amygdala; BLA and BMA, basolateral and basomedial nuclei of the amygdala, respectively; CPu, caudate putamen; GP, globus pallidus; ic, internal capsule.
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Related In: Results  -  Collection

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Figure 9: Trace 50-250 CRs were amygdala-dependent in mice, with no residual CR components. A, Bilateral infusions of muscimol (1mm, 100–150 nl) were used to inactivate the anterior central nuclei of the amygdala in 6 trained mice (left). The expression of CRs were nearly abolished (2–9% CR rates) during infusion sessions in all 6 mice (right graph, red markers; paired t = 14.27, df = 5, p < 0.001), whereas the CR rates observed during control infusions were not different than preinfusion sessions (cyan markers; t = 2.34, p = 0.07). B, Example behavior from muscimol (denoted by red text) and control sessions (cyan text) for two mice. Note the significant decrease in the expression of CRs during muscimol infusion sessions, while behavior during control sessions was less globally affected by the infusion procedure. Br, Bregma; CeA, central nucleus of the amygdala; BLA and BMA, basolateral and basomedial nuclei of the amygdala, respectively; CPu, caudate putamen; GP, globus pallidus; ic, internal capsule.
Mentions: In addition to sometimes driving a noncerebellar learned eyelid response (see Introduction), it has also been suggested that the amygdala may facilitate other inputs to the pons and enhance the neural representation of the CS before being projected to the cerebellum. As a follow-up to the cerebellar inactivation experiment, we tested the amygdala-dependence of learned responses for trace 50–250 by infusing muscimol into the central nucleus after training to asymptotic performance (6/7 implanted mice learned, preinfusion mean = 70 ± 5% CR rate). Inactivation resulted in significant decreases in the expression of CRs in all six mice (infusion session mean = 5 ± 1% CR rate, paired t = 14.27, df = 5, p < 0.001y; Fig. 9A, right, example behavioral sessions given in B, left). Control infusions did not reliably affect the expression of CRs using the same procedures (precontrol infusion mean = 77 ± 5% CR rate, control infusion mean = 59 ± 8% CR rate; paired t = 2.34, df = 5, p = 0.07z; Fig. 9A, right; examples given in B, right). Because the CRs in our trained mice are dominated by a well timed response that is reminiscent of the previously reported cerebellar component (Koekkoek et al., 2005; Sakamoto and Endo, 2010), and given the known hodology, we interpret these results as suggesting that the amygdala, like the mPFC and primary sensory regions, may provide a CS-associated input to the cerebellum that supports the learning and ongoing cerebellar expression of CRs.

Bottom Line: To identify the circuitry involved, we made restricted lesions of the medial prefrontal cortex (mPFC) and found that learning was prevented.Anatomical data from these critical regions showed that mPFC and amygdala both project to the rostral basilar pons and overlap with eyelid-associated pontocerebellar neurons.The data further reveal a specific role for the amygdala as providing a conditioned stimulus-associated input to the cerebellum.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Learning and Memory, University of Texas at Austin , Austin, Texas 78712.

ABSTRACT
Trace eyeblink conditioning is useful for studying the interaction of multiple brain areas in learning and memory. The goal of the current work was to determine whether trace eyeblink conditioning could be established in a mouse model in the absence of elicited startle responses and the brain circuitry that supports this learning. We show here that mice can acquire trace conditioned responses (tCRs) devoid of startle while head-restrained and permitted to freely run on a wheel. Most mice (75%) could learn with a trace interval of 250 ms. Because tCRs were not contaminated with startle-associated components, we were able to document the development and timing of tCRs in mice, as well as their long-term retention (at 7 and 14 d) and flexible expression (extinction and reacquisition). To identify the circuitry involved, we made restricted lesions of the medial prefrontal cortex (mPFC) and found that learning was prevented. Furthermore, inactivation of the cerebellum with muscimol completely abolished tCRs, demonstrating that learned responses were driven by the cerebellum. Finally, inactivation of the mPFC and amygdala in trained animals nearly abolished tCRs. Anatomical data from these critical regions showed that mPFC and amygdala both project to the rostral basilar pons and overlap with eyelid-associated pontocerebellar neurons. The data provide the first report of trace eyeblink conditioning in mice in which tCRs were driven by the cerebellum and required a localized region of mPFC for acquisition. The data further reveal a specific role for the amygdala as providing a conditioned stimulus-associated input to the cerebellum.

No MeSH data available.


Related in: MedlinePlus