Timing correlations between cerebellar interpositus neuronal firing and classically conditioned eyelid responses in wild-type and Lurcher mice

Abstract

Classical eyeblink conditioning is an experimental model widely used for the study of the neuronal mechanisms underlying the acquisition of new motor and cognitive skills. There are two principal interpretations of the role of the cerebellum in the learning of eyelid conditioned responses (CRs). One considers that the cerebellum is the place where this learning is acquired and stored, while the second suggests that the cerebellum is mostly involved in the proper performance of acquired CRs, implying that there must be other brain areas involved in the learning process. We checked the timing of cerebellar interpositus nucleus (IPN) neurons’ firing rate with eyelid CRs in both wild-type (WT) and Lurcher (a model of cerebellar cortex degeneration) mice. We used delay and trace conditioning paradigms. WT mice presented a better execution for delay vs. trace conditioning and also for these two paradigms than did Lurcher mice. IPN neurons were activated during CRs following the activation of the orbicularis oculi muscle. Firing patterns of IPN neurons were altered in Lurcher mice. In conclusion, the cerebellum seems to be mostly related with the performance of conditioned responses, rather than with their acquisition.

Inactivation of the interpositus nucleus blocks the acquisition of conditioned responses and timing changes in conditioning-specific reflex modification of the rabbit eyeblink response

“…Because of the overlap between some features of CRs and CRM, a strong neural candidate for CRM acquisition is the interpositus (IP) nucleus of the cerebellum, which is a major site for the integration of CS and US inputs with outputs controlling the generation of the rabbit eyeblink CR (Gonzalez-Joekes and Schreurs, 2012; Gould, Sears, & Steinmetz, 1993; Ostrowska, Zguczynski, & Zimny, 1992; Steinmetz and Sengelaub, 1992; Thompson, 2013). There is general consensus that the IP is necessary for the acquisition of eyeblink conditioning, as indicated by IP lesion and inactivation studies showing severe impairments to CR acquisition and electrophysiological studies demonstrating the development of learning-related neuronal activity in the IP closely associated with the execution of the CR ( for review, see Christian and Thompson, 2003; Freeman and Steinmetz, 2011; but see also Ammann, Marquez-Ruiz, Gomez-Climent, Delgado-Garcia, & Gruart, 2016; López-Ramos, Houdek, Cendelín, Vožeh, & Delgado-García, 2018). Of particular relevance is work showing that CRM-like increases in the amplitude of the UR in well-trained rabbits is blocked or disfacilitated by IP inactivation, suggesting a role of the IP in CRM expression (Wikgren and Korhonen, 2001).…”

Role of the motor cortex in the generation of classically conditioned eyelid and vibrissae responses

“…Following previous experimental procedures from our laboratory 14 we carried out a timing correlation analysis to determine temporal differences between the initiation of firing of MC neurons, the OO and Vib rEMGs, and eyelid position, during the performance of CRs. For this analysis, we prepared 6 new channels copying one of each pair of the compared channels (the OO rEMG trace in the example illustrated in Fig.…”

“…In all of the cases, we used the comparison OO rEMG vs. eyelid movement (Fig. 5 f) as a proper control of the analytical procedures, since muscle activity must precede eyelid movements by a fix time interval 5 , 14 , 16 , 22 , 39 .

Figure 5 Timing correlation between MC neuron firing rate, OO rEMG, Vib rEMG, and lower-eyelid position, during eyeblink and vibrissae conditioning with a delay paradigm.

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“…Following the mathematical models of Marr 6 and Albus 7 , the experimental studies of Thompson’s group 8 , 9 were the first to assign to the cerebellum an essential role in classical eyeblink conditioning, whereas other authors sustained that cerebellar structures have a role in the proper performance of eyelid responses, but not in its acquisition and storage 10 – 13 . In relation to these seminal studies, we used timing correlation analysis aimed to test whether the cerebellar interpositus nucleus of classically conditioned mice is the origin of eyelid CRs 14 ; collected results suggested that Type A interpositus neurons 12 do not seem to be the place where CRs are generated.…”

“…Eyelid position was determined with the help of a magnetic recording technique. We used a tone as CS, and the same air-puff as US, to stimulate eyelid and Vib simultaneously, with the aim of carrying out a timing correlation analysis 14 , 39 between the two EMGs, the eyelid position, and the unitary activity of identified MC neurons. Furthermore, we have recorded the movement of the eyelid to study its kinematics and to include it in the timing correlation analysis, with the aim of revealing whether the MC area is the place where the CR is originated.…”