Medial Auditory Thalamus Is Necessary for Expression of Auditory Trace Eyelid Conditioning.

Transforming a brief sensory event into a persistent neural response represents a mechanism for linking temporally disparate stimuli together to support learning. The cerebellum requires this type of persistent input during trace conditioning to engage associative plasticity and acquire adaptively timed conditioned responses (CRs). An initial step toward identifying the sites and mechanisms generating and transmitting persistent signals to the cerebellum is to identify the input pathway. The medial auditory thalamic nuclei (MATN) are the necessary and sufficient source of auditory input to the cerebellum for delay conditioning in rodents and a possible input to forebrain sites generating persistent signals. Using pharmacological and computational approaches, we test (1) whether the necessity of MATN during auditory eyelid conditioning is conserved across species, (2) whether the MATN are necessary for the expression of trace eyelid CRs, and if so, (3)whether this relates to the generation of persistent signals. We find that contralateral inactivation of MATN with muscimol largely abolished trace and delay CRs in male rabbits. Residual CRs were decreased in amplitude, but CR timing was unaffected. Results from large-scale cerebellar simulations are consistent with previous experimental demonstrations that silencing only CS-duration inputs does not abolish trace CRs, and instead affects their timing. Together, these results suggest that the MATN are a necessary component of both the direct auditory stimulus pathway to the cerebellum and the pathway generating task-essential persistent signals.SIGNIFICANCE STATEMENT Persistent activity is required for working memory-dependent tasks, such as trace conditioning, and represents a mechanism by which sensory information can be used over time for learning and cognition. This neuronal response entails the transformation of a discrete sensory-evoked response into a signal that extends beyond the stimulus event. Understanding the generation and transmission of this stimulus transformation requires identifying the input sources necessary for task-essential persistent signals. We report that the medial auditory thalamic nuclei are required for the expression of auditory trace conditioning and suggest that these nuclei are a component of the pathway-generating persistent signals. Our study provides a foundation for testing circuit-level mechanisms underlying persistent activity in a cerebellar learning model with identified inputs and well defined behavioral outputs.

Systematic variation of acquisition rate in delay eyelid conditioning.

Averaging artifacts inherent in group acquisition curves can mask behavioral phenomena that are potentially revealing in terms of underlying neural mechanisms. To address this, we implemented a behavioral analysis of 106 rabbits trained over 4 sessions using delay eyelid conditioning. Group results showed the typical monotonic increase in conditioned responses (CRs). For most subjects CRs first appeared (as indexed by the criterion of 8 CRs in 9 trials) during the first 18 trials of the second training session. Subdividing subjects according to the training block at which they met criterion revealed systematic differences in the subsequent rate that CR amplitudes increased, but not in asymptotic CR amplitudes. Subjects meeting criterion early in sessions showed more rapid increases in CR amplitude than those meeting criterion later in sessions. This effect was solely dependent on how early within a session criterion was met, as subjects meeting criterion at the beginning of the third and fourth sessions showed more rapid increases in CR amplitude than those meeting criterion after the first 18 trials of the second session. The exceptions were the 7% of the subjects that met criterion late in the first session. Their CR amplitudes increased at a rate similar to subjects meeting criterion early in sessions. These results suggest an interplay between consolidation processes and a previously reported short-term plasticity process that makes CR acquisition a nonmonotonic and complex function of the point during training sessions at which CRs first appear. (PsycINFO Database Record

Harnessing the power of theta: natural manipulations of cognitive performance during hippocampal theta-contingent eyeblink conditioning.

Neurobiological oscillations are regarded as essential to normal information processing, including coordination and timing of cells and assemblies within structures as well as in long feedback loops of distributed neural systems. The hippocampal theta rhythm is a 3-12 Hz oscillatory potential observed during cognitive processes ranging from spatial navigation to associative learning. The lower range, 3-7 Hz, can occur during immobility and depends upon the integrity of cholinergic forebrain systems. Several studies have shown that the amount of pre-training theta in the rabbit strongly predicts the acquisition rate of classical eyeblink conditioning and that impairment of this system substantially slows the rate of learning. Our lab has used a brain-computer interface (BCI) that delivers eyeblink conditioning trials contingent upon the explicit presence or absence of hippocampal theta. A behavioral benefit of theta-contingent training has been demonstrated in both delay and trace forms of the paradigm with a two- to four-fold increase in learning speed. This behavioral effect is accompanied by enhanced amplitude and synchrony of hippocampal local field potential (LFP)s, multi-unit excitation, and single-unit response patterns that depend on theta state. Additionally, training in the presence of hippocampal theta has led to increases in the salience of tone-induced unit firing patterns in the medial prefrontal cortex, followed by persistent multi-unit activity during the trace interval. In cerebellum, rhythmicity and precise synchrony of stimulus time-locked LFPs with those of hippocampus occur preferentially under the theta condition. Here we review these findings, integrate them into current models of hippocampal-dependent learning and suggest how improvement in our understanding of neurobiological oscillations is critical for theories of medial temporal lobe processes underlying intact and pathological learning.

Hippocampal theta-dependent eyeblink classical conditioning: coordination of a distributed learning system.

Richard F. Thompson's study of the neurobiological substrates of learning and memory has been a career-long endeavor, chosen early and pursued with uncompromising depth and breadth. His systematic mapping of the major brain systems and mechanisms involved in eyeblink classical conditioning (EBCC) established the essential role of the cerebellum. Investigations of the interactions between the hippocampus and cerebellum are critically important to this literature, given the essential involvement of these structures in trace EBCC as well as an important modulatory role of the hippocampus in delay EBCC. Hippocampal theta (3-7Hz) oscillations are known to reflect a functional state that influences both the timing of unit firing and the potential for neural plasticity in the hippocampus and other structures. Herein we present a brief summary of research demonstrating the behavioral enhancement due to theta and the underlying neurobiological correlates in both hippocampus and cerebellum during EBCC. Hippocampal and cerebellar local field potentials (LFPs) show that these distantly interconnected brain structures become precisely synchronized when conditions favor rapid behavioral acquisition. Our results suggest a major role for theta in coordinating the widely distributed memory system for trace EBCC. These and other important findings reflect Thompson's own work and his early-career mentoring of scientists whose contributions to the EBCC literature have ensured his major and lasting impact on the neurobiology of learning and memory.

Cerebellar theta oscillations are synchronized during hippocampal theta-contingent trace conditioning.

The hippocampus and cerebellum are critically involved in trace eyeblink classical conditioning (EBCC). The mechanisms underlying the hippocampal-cerebellar interaction during this task are not well-understood, although hippocampal theta (3-7 Hz) oscillations are known to reflect a favorable state for EBCC. Two groups of rabbits received trace EBCC in which a brain-computer interface administered trials in either the explicit presence or absence of naturally occurring hippocampal theta. A high percentage of robust theta led to a striking enhancement of learning accompanied by rhythmic theta-band (6-7 Hz) oscillations in the interpositus nucleus (IPN) and cerebellar cortex that were time-locked both to hippocampal rhythms and sensory stimuli during training. Rhythmic oscillations were absent in the cerebellum of the non-theta group. These data strongly suggest a beneficial impact of theta-based coordination of hippocampus and cerebellum and, importantly, demonstrate that hippocampal theta oscillations can be used to index, and perhaps modulate, the functional properties of the cerebellum.