Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice

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.

Enhanced Acquisition and Retention of Conditioned Eyeblink Responses in Veterans Expressing PTSD Symptoms: Modulation by Lifetime History of Mild Traumatic Brain Injury

Enhanced acquisition of eyeblink conditioning is observed in active duty military and veterans expressing PTSD symptoms (PTSD+) and those expressing temperamental vulnerabilities to develop PTSD after traumatic experiences, such as behaviorally inhibited temperament. There is a growing literature showing persistent cerebellar abnormalities in those experiencing mild traumatic brain injury (mTBI+) as well as linkages between mTBI and PTSD. With the dependency of eyeblink conditioning on cerebellar processes, the impact of mTBI on eyeblink conditioning in veterans expressing PTSD is unknown. The present study assessed eyeblink conditioning in veterans during two sessions separated by 1 week. With a focus on the accelerated learning of veterans expressing PTSD, training utilized a protocol which degrades learning through interspersing conditioned stimulus (CS) exposures amongst delay-type trials of CS and unconditional stimulus (US) co-terminating trials. Faster acquisition of the eyeblink conditioned responses (CR) was observed in PTSD during Week 1. The Week 2 assessment revealed an interaction of mTBI and PTSD, such that asymptotic performance of PTSD+ was greater than PTSD− among mTBI− veterans, whereas these groups did not differ in mTBI+ veterans. To further examine the relationship between enhanced sensitivity to acquire eyeblink conditioning and PTSD, cluster analysis was performed based on performance across training sessions. Those with enhanced sensitivity to acquire eyeblink conditioned responses expressed more PTSD symptoms, which were specific to Cluster C symptoms of avoidance, in addition to greater behavioral inhibition. These results support the continued investigation of the conditioned eyeblink response as a behavioral indicator of stress-related psychopathology.

Long-term effects of cerebellar anodal transcranial direct current stimulation (tDCS) on the acquisition and extinction of conditioned eyeblink responses

Cerebellar transcranial direct current stimulation (tDCS) has been reported to enhance the acquisition of conditioned eyeblink responses (CR), a form of associative motor learning. The aim of the present study was to determine possible long-term effects of cerebellar tDCS on the acquisition and extinction of CRs. Delay eyeblink conditioning was performed in 40 young and healthy human participants. On day 1, 100 paired CS (conditioned stimulus)–US (unconditioned stimulus) trials were applied. During the first 50 paired CS–US trials, 20 participants received anodal cerebellar tDCS, and 20 participants received sham stimulation. On days 2, 8 and 29, 50 paired CS–US trials were applied, followed by 30 CS-only extinction trials on day 29. CR acquisition was not significantly different between anodal and sham groups. During extinction, CR incidences were significantly reduced in the anodal group compared to sham, indicating reduced retention. In the anodal group, learning related increase of CR magnitude tended to be reduced, and timing of CRs tended to be delayed. The present data do not confirm previous findings of enhanced acquisition of CRs induced by anodal cerebellar tDCS. Rather, the present findings suggest a detrimental effect of anodal cerebellar tDCS on CR retention and possibly CR performance.

NMDAR-dependent emergence of behavioral representation in primary visual cortex

Neocortical sensory areas are generally thought to faithfully represent external stimuli. However, a growing body of evidence suggests that cortical networks exhibit considerable functional plasticity over multiple temporal scales, allowing them to modify their output to reflect ongoing behavioral demands. Nevertheless, the dynamics of sensory and non-sensory representations during acquisition of stimulus-guided behavior are not well understood. We performed longitudinal 2-photon imaging of activity in primary visual cortex (V1) of mice learning a conditioned eyeblink task. We found that both excitatory and inhibitory neurons robustly encode the visual stimulus throughout training despite a significant experience-dependent reduction in response magnitude. In contrast, both pyramidal neurons and parvalbumin-expressing interneurons exhibit emergence of behavioral representation during learning. The plasticity of visual response magnitude and behavioral representation is abolished following loss of NMDA-type glutamate receptors. Overall, our findings demonstrate that V1 networks can dynamically multiplex distinct behaviorally relevant representations over the course of learning.