The cerebellum is a critical component of the motor system as revealed by the severe motor dysfunction seen with cerebellar pathology. The objective of our work is to determine the mechanisms by which the synaptic organization of the cerebellum contributes to motor function. To accomplish this we will use a relatively simple form of motor learning; classical conditioning of eyelid responses in rabbit. Eyelid conditioning offers numerous advantages as an experimental preparation. In particular, the way in which the stimuli used in conditioning activate cerebellar afferents provides a powerful yet simple means to study the input/out properties of the cerebellum. These advantages will be used to address three fundamentally important issues: 1) what are the loci of synaptic plasticity in the cerebellum that contribute to motor learning; 2) what factors control the induction of this plasticity; 3) how does this plasticity, in combination with the synaptic organization of the cerebellum, contribute to the learning and to the expression of movements.
Five specific aims are proposed. 1) Determine cerebellar involvement of the timing of conditioned movements. These studies extend preliminary data indicating that response timing is severely disrupted by cerebellar cortex lesions. This suggests that conditioning is mediated by synaptic plasticity at two cerebellar sites, and how these sites contribute in parallel to the expression of movements. 2) Characteristics cerebellar neuron activity during the execution of differently timed conditioned movements. These studies will use single unit recordings to study the cerebellar cortex processing contributing to response timing. 3) Determine the role of the cerebellar cortex in extinction of conditioned movements. These studies are based on preliminary data suggesting the cerebellar cortex is required for extinction of conditioned responses. These experiments address the fundamental issue of whether the cerebellar cortex is involved with or necessary for the learning of movements. 4) Identify the loci of synaptic plasticity responsible for motor learning. These studies combine stimulation and unit recordings to distinguish between cerebellar and post-cerebellar sites of synaptic plasticity in motor learning. These studies will help resolve ongoing debates concerning the role of cerebellar synaptic plasticity in motor learning. 5) Characterize expectancy-related modulation of climbing fibers. These studies use various type of conditioning trials to study spontaneous and stimulus-evoked climbing fiber responses when stimuli are expected and when they are expected. This is central to the putative role of climbing fibers as an error signal which induces cerebellar plasticity essential for motor learning. Completion of these aims will help identify cerebellar sites of synaptic plasticity, how this plasticity is involved in both the learning and the execution of movements, and how together these mechanisms permit movements to be adaptively modified by experience to improve motor performance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH046904-04
Application #
2247313
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1992-05-01
Project End
1997-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Khilkevich, Andrei; Zambrano, Juan; Richards, Molly-Marie et al. (2018) Cerebellar implementation of movement sequences through feedback. Elife 7:
Khilkevich, Andrei; Halverson, Hunter E; Canton-Josh, Jose Ernesto et al. (2016) Links Between Single-Trial Changes and Learning Rate in Eyelid Conditioning. Cerebellum 15:112-21
Halverson, Hunter E; Khilkevich, Andrei; Mauk, Michael D (2015) Relating cerebellar purkinje cell activity to the timing and amplitude of conditioned eyelid responses. J Neurosci 35:7813-32
Siegel, Jennifer J (2014) Modification of persistent responses in medial prefrontal cortex during learning in trace eyeblink conditioning. J Neurophysiol 112:2123-37
Moya, Maria V; Siegel, Jennifer J; McCord, Eedann D et al. (2014) Species-specific differences in the medial prefrontal projections to the pons between rat and rabbit. J Comp Neurol 522:3052-74
Siegel, Jennifer J; Mauk, Michael D (2013) Persistent activity in prefrontal cortex during trace eyelid conditioning: dissociating responses that reflect cerebellar output from those that do not. J Neurosci 33:15272-84
Kalmbach, Brian E; Mauk, Michael D (2012) Multiple sites of extinction for a single learned response. J Neurophysiol 107:226-38
Kalmbach, Brian E; Voicu, Horatiu; Ohyama, Tatsuya et al. (2011) A subtraction mechanism of temporal coding in cerebellar cortex. J Neurosci 31:2025-34
Ohyama, Tatsuya; Voicu, Horatiu; Kalmbach, Brian et al. (2010) A decrementing form of plasticity apparent in cerebellar learning. J Neurosci 30:16993-7003
Kalmbach, Brian E; Davis, Tobin; Ohyama, Tatsuya et al. (2010) Cerebellar cortex contributions to the expression and timing of conditioned eyelid responses. J Neurophysiol 103:2039-49

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