A method for combining multiple-units readout of optogenetic control with natural stimulation-evoked eyeblink conditioning in freely-moving mice

Zhang, Jie; Zhang, Kai-Yuan; Zhang, Libin; Zhang, Weiwei; Feng, Hua; Yao, Zhong-Xiang; Hu, Bo; Chen, Hao

doi:10.1038/s41598-018-37885-w

Cited by 6 publications

(7 citation statements)

References 64 publications

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“…Stimulus generalization has been studied previously using fear conditioning. However, to our knowledge, a complete assessment of conditioned fear responses as a function of a wide range of tone frequency is missing: all studies probed generalization of fear responses presenting only one or a few novel auditory cue(s) ( Shaban et al, 2006 ; Zhang et al, 2019 ). In addition, most fear conditioning studies use a differential paradigm during acquisition.…”

Section: Discussionmentioning

confidence: 99%

“…Given the advance of transgenics and optogenetics ( Deisseroth, 2011 ; Boyden, 2015 ; Navabpour et al, 2020 ), mice have become an increasingly popular animal model model to study mechanisms underlying cerebellar learning ( Alba, 1994 ; Heiney et al, 2014 ; Kloth et al, 2015 ; Gao et al, 2016 ; Albergaria et al, 2018 ; Zhang et al, 2019 ). This also holds for Pavlovian eyeblink conditioning, a behavioral test that allows for wide variations in parameter space, including those of onset, duration and intensity of both conditional stimulus (CS) and unconditional stimulus (US; Alba, 1994 ; Chettih et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

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Stimulus Generalization in Mice during Pavlovian Eyeblink Conditioning

Fiocchi

Dijkhuizen

Koekkoek

et al. 2022

eNeuro

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Here we investigate stimulus generalization in a cerebellar learning paradigm, called eyeblink conditioning. Mice were conditioned to close their eyes in response to a 10 kHz tone by repeatedly pairing this tone with an air puff to the eye 250 ms after tone onset. After ten consecutive days of training, when mice showed reliable conditioned eyelid responses to the 10 kHz tone, we started to expose them to tones with other frequencies, ranging from 2 to 20 kHz. We found that mice had a strong generalization gradient, whereby the probability and amplitude of conditioned eyelid responses gradually decreases depending on the dissimilarity with the 10 kHz tone. Tones with frequencies closest to 10kHz evoked the most and largest conditioned eyelid responses and each step away from the 10 kHz tone resulted in fewer and smaller conditioned responses. In addition, we found that tones with lower frequencies resulted in conditioned responses that peaked earlier after tone onset compared to those to tones with higher frequencies. Together, our data show prominent generalization patterns in cerebellar learning. Since the known function of cerebellum is rapidly expanding from pure motor control to domains that include cognition, reward-learning, fear-learning, social function, and even addiction, our data implies generalization controlled by cerebellum in all these domains. Significance Statement: Conditioned stimuli that resemble each other will evoke a rather similar behavioral response. Here, we investigate this phenomenon of stimulus generalization using Pavlovian eyeblink conditioning to probe cerebellar function. Cerebellum is a brain structure whose known function is rapidly expanding from pure motor control to domains that include cognition, reward-learning, fear-learning, social function, and even addiction. Since we found a strong generalization of the auditory stimulus in eyeblink conditioning, our data implies an important role for generalization in motor and non-motor domains. Methods SubjectsWe used 14 wild-type C57Bl/6 mice, 7 of which were male and 7 were female. Mice were between 11-16 weeks old at the start of the experiment. All mice were housed individually during the experiment with food and water ad libitum in a 12:12 light/dark cycle. Experiments were performed during the light phase. All experiments were performed in accordance with the European Communities Council Directive. Protocols were reviewed and approved by the Erasmus Laboratory Animal Science Center (work protocol nr. 15-273-138; project license nr. AVD101002015273) Auditory Brainstem Responses Since C57Bl/6 mice are prone for developing hearing problems, we recorded prior to the start of eyeblink conditioning training the auditory brainstem responses (ABRs) to obtain hearing level thresholds. Mice were anesthetized with a ketamine/xylazine mixture at a dose of 100/10 mg/kg body weight, administered intraperitoneally (ketamine: Alfasan, Woerden, NL; xylazine: Sedazine®, AST Farma, Oudewater, NL). After this, they were placed in a soundand ligh...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stimulus Generalization in Mice during Pavlovian Eyeblink Conditioning

Fiocchi

Dijkhuizen

Koekkoek

et al. 2022

eNeuro

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“…S2). Hippocampal INs have been reported to exhibit high discharge rates (>6 Hz) and narrow spike width (valley-to-peak width ≤0.35-ms) [ 29 , 33 ]. By using these criteria, 104 putative INs were identified in the mice with CS-US paired presentation (across 12 mice, average 8.7 units per mouse, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…After 4 weeks of post-injection viral expression, diode-tetrode assemblies were implanted bilaterally into the dorsal hippocampus of GAD2-cre mice (AP: − 1.9 mm, ML: ± 1.6 mm, DV: 1.0 mm). Fabrication of the diode-tetrode assembly has been previously described in detail [ 29 ]. Briefly, a 200-μm optic fiber (0.37 NA, FT200EMT, Thorlabs, Germany) was combined with the tetrode array.…”

Section: Methodsmentioning

confidence: 99%

“…Single units were classified into either putative pyramidal cells (Pyrs) or interneurons (INs) based on their firing rate and waveform (i.e., the trough-to-peak duration and spike width). Units with an average firing rate <6 Hz and a peak-to-trough duration >0.35-ms were classified as putative Pyrs, while units with an average firing rate ≥6 Hz and a peak-to-trough duration ≤0.35-ms were classified as putative INs [ 29 , 33 ]. The spikes recorded during each valid trial were assigned to 50-ms time bins, beginning 1000-ms before and extending 1000-ms after the CS onset.…”

Section: Methodsmentioning

confidence: 99%

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Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice

Zhang

et al. 2021

Neurosci. Bull.

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While the hippocampus has been implicated in supporting the association among time-separated events, the underlying cellular mechanisms have not been fully clarified. Here, we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning (tEBC) task. We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the tEBC. Consistent with this, greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC. Moreover, optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC. In contrast, suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs. Our findings highlight the role of hippocampal interneurons in the tEBC, and point to a potential cellular mechanism subserving associative learning.

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