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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.


Related in: MedlinePlus

Mice efficiently extinguished learned responses, and showed savings during reacquisition. A, CR rates for mice during asymptotic performance (Pre), and for extinction and reacquisition sessions. Mice (n = 9) decreased CR rates to <5% within three extinction sessions, and reacquired CRs faster than during initial acquisition (“savings”; left graph, red markers show median CR rate for each session). Decreases in CR rate were accompanied by decreases in amplitude (middle graph, median ± IQR, t = 3.21, df = 8, p = 0.01), but not by differences in CR peak latencies (right graph, median ± IQR, t = 0.10, p = 0.92). B, Example extinction and reacquisition sessions from two mice. For extinction, some mice decreased CRs gradually (top) while others showed more abrupt changes in behavior (middle). Note the decrease in CR amplitude during extinction sessions, whereas the timing of CRs was maintained. All mice met learning criterion (>50% CRs) within one to three reacquisition sessions. Some mice showed gradual learning during a session (top), whereas others increased expression between sessions (bottom).
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Figure 5: Mice efficiently extinguished learned responses, and showed savings during reacquisition. A, CR rates for mice during asymptotic performance (Pre), and for extinction and reacquisition sessions. Mice (n = 9) decreased CR rates to <5% within three extinction sessions, and reacquired CRs faster than during initial acquisition (“savings”; left graph, red markers show median CR rate for each session). Decreases in CR rate were accompanied by decreases in amplitude (middle graph, median ± IQR, t = 3.21, df = 8, p = 0.01), but not by differences in CR peak latencies (right graph, median ± IQR, t = 0.10, p = 0.92). B, Example extinction and reacquisition sessions from two mice. For extinction, some mice decreased CRs gradually (top) while others showed more abrupt changes in behavior (middle). Note the decrease in CR amplitude during extinction sessions, whereas the timing of CRs was maintained. All mice met learning criterion (>50% CRs) within one to three reacquisition sessions. Some mice showed gradual learning during a session (top), whereas others increased expression between sessions (bottom).

Mentions: Mice also displayed flexible learning. Mice learned not to respond during sessions in which the light was no longer paired with the air puff (i.e., extinction training), with CR expression fully extinguished in all mice by the third day (0–5% CRs, n = 9, Fig. 5A, left). The CRs expressed by some mice extinguished slowly, with gradually decreasing CR amplitudes (Fig. 5B, top), whereas the CRs of other mice extinguished quickly, after only a few CS-only trials (Fig. 5B, bottom). In general, extinction appeared to be associated with a decrease in CR amplitude (pre-extinction mean = 0.36 ± 0.06 FEC, extinction day 1 mean = 0.21 ± 0.02 FEC; paired t = 3.21, df = 8, p = 0.01s; Fig. 5A, middle graph), whereas the timing of CRs was not different than before extinction training (pre-extinction mean = 307 ± 6 ms, extinction day 1 mean = 308 ± 11 ms; paired t = 0.10, df = 8, p = 0.92t; Fig. 5A, right graph). When paired trials were reinstated (reacquisition training), all mice showed behavioral savings and reacquired CRs much faster than original acquisition (within 1–3 sessions; Fig. 5A, left, B). By the second reacquisition session mice showed similar CR amplitudes and timing relative to pre-extinction training (Amplitude: reacquisition mean = 0.37 ± 0.09 ms, paired t = 0.17, df = 7, p = 0.87u; Latency to CR Peak: reacquisition mean = 303 ± 16 ms, paired t = 0.18, df = 7, p = 0.86v; one mouse did not show sufficient CRs during probe trials to calculate median measures and was not included in the latter comparisons; Fig. 5A, middle and right graphs). The data show that in addition to learning a trace 50–250 eyeblink conditioning task, mice can also learn not to respond and that the learned behavior can be efficiently reinstated through experience.


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)

Mice efficiently extinguished learned responses, and showed savings during reacquisition. A, CR rates for mice during asymptotic performance (Pre), and for extinction and reacquisition sessions. Mice (n = 9) decreased CR rates to <5% within three extinction sessions, and reacquired CRs faster than during initial acquisition (“savings”; left graph, red markers show median CR rate for each session). Decreases in CR rate were accompanied by decreases in amplitude (middle graph, median ± IQR, t = 3.21, df = 8, p = 0.01), but not by differences in CR peak latencies (right graph, median ± IQR, t = 0.10, p = 0.92). B, Example extinction and reacquisition sessions from two mice. For extinction, some mice decreased CRs gradually (top) while others showed more abrupt changes in behavior (middle). Note the decrease in CR amplitude during extinction sessions, whereas the timing of CRs was maintained. All mice met learning criterion (>50% CRs) within one to three reacquisition sessions. Some mice showed gradual learning during a session (top), whereas others increased expression between sessions (bottom).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596016&req=5

Figure 5: Mice efficiently extinguished learned responses, and showed savings during reacquisition. A, CR rates for mice during asymptotic performance (Pre), and for extinction and reacquisition sessions. Mice (n = 9) decreased CR rates to <5% within three extinction sessions, and reacquired CRs faster than during initial acquisition (“savings”; left graph, red markers show median CR rate for each session). Decreases in CR rate were accompanied by decreases in amplitude (middle graph, median ± IQR, t = 3.21, df = 8, p = 0.01), but not by differences in CR peak latencies (right graph, median ± IQR, t = 0.10, p = 0.92). B, Example extinction and reacquisition sessions from two mice. For extinction, some mice decreased CRs gradually (top) while others showed more abrupt changes in behavior (middle). Note the decrease in CR amplitude during extinction sessions, whereas the timing of CRs was maintained. All mice met learning criterion (>50% CRs) within one to three reacquisition sessions. Some mice showed gradual learning during a session (top), whereas others increased expression between sessions (bottom).
Mentions: Mice also displayed flexible learning. Mice learned not to respond during sessions in which the light was no longer paired with the air puff (i.e., extinction training), with CR expression fully extinguished in all mice by the third day (0–5% CRs, n = 9, Fig. 5A, left). The CRs expressed by some mice extinguished slowly, with gradually decreasing CR amplitudes (Fig. 5B, top), whereas the CRs of other mice extinguished quickly, after only a few CS-only trials (Fig. 5B, bottom). In general, extinction appeared to be associated with a decrease in CR amplitude (pre-extinction mean = 0.36 ± 0.06 FEC, extinction day 1 mean = 0.21 ± 0.02 FEC; paired t = 3.21, df = 8, p = 0.01s; Fig. 5A, middle graph), whereas the timing of CRs was not different than before extinction training (pre-extinction mean = 307 ± 6 ms, extinction day 1 mean = 308 ± 11 ms; paired t = 0.10, df = 8, p = 0.92t; Fig. 5A, right graph). When paired trials were reinstated (reacquisition training), all mice showed behavioral savings and reacquired CRs much faster than original acquisition (within 1–3 sessions; Fig. 5A, left, B). By the second reacquisition session mice showed similar CR amplitudes and timing relative to pre-extinction training (Amplitude: reacquisition mean = 0.37 ± 0.09 ms, paired t = 0.17, df = 7, p = 0.87u; Latency to CR Peak: reacquisition mean = 303 ± 16 ms, paired t = 0.18, df = 7, p = 0.86v; one mouse did not show sufficient CRs during probe trials to calculate median measures and was not included in the latter comparisons; Fig. 5A, middle and right graphs). The data show that in addition to learning a trace 50–250 eyeblink conditioning task, mice can also learn not to respond and that the learned behavior can be efficiently reinstated through experience.

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