Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning

Abstract

Siegel JJ, Kalmbach B, Chitwood RA, Mauk MD. Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning. J Neurophysiol 107: 50-64, 2012. First published September 28, 2011 doi:10.1152/jn.00689.2011We have addressed the source and nature of the persistent neural activity that bridges the stimulusfree gap between the conditioned stimulus (CS) and unconditioned stimulus (US) during trace eyelid conditioning. Previous work has demonstrated that this persistent activity is necessary for trace eyelid conditioning: CS-elicited activity in mossy fiber inputs to the cerebellum does not extend into the stimulus-free trace interval, which precludes the cerebellar learning that mediates conditioned response expression. In behaving rabbits we used in vivo recordings from a region of medial prefrontal cortex (mPFC) that is necessary for trace eyelid conditioning to test the hypothesis that neurons there generate activity that persists beyond CS offset. These recordings revealed two patterns of activity during the trace interval that would enable cerebellar learning. Activity in some cells began during the tone CS and persisted to overlap with the US, whereas in other cells, activity began during the stimulus-free trace interval. Injection of anterograde tracers into this same region of mPFC revealed dense labeling in the pontine nuclei, where recordings also revealed tone-evoked persistent activity during trace conditioning. These data suggest a corticopontine pathway that provides an input to the cerebellum during trace conditioning trials that bridges the temporal gap between the CS and US to engage cerebellar learning. As such, trace eyelid conditioning represents a well-characterized and experimentally tractable system that can facilitate mechanistic analyses of cortical persistent activity and how it is used by downstream brain structures to influence behavior. single units; medial prefrontal cortex; classical conditioning; pontine nuclei; dextran tracer THE ABILITY TO USE PRIOR ASSOCIATIVE learning to predict events and guide actions is essential to survival. Because events are often separated in time, the neural mechanisms of forming associations between events that do not overlap in time are of particular interest. Several forebrain regions appear to be specialized for this purpose, because they contain neurons capable of generating activity that persists beyond the termination of one stimulus to overlap in time with an associated second stimulus. These persistent responses, such as those observed in primate prefrontal cortex during delayed-response tasks, are hypothesized to contribute to working memory and other cognitive processes by maintaining spike activity between a cue and the later reinforcement that it predicts (Curtis 2006; Frank and Brown 2003;Fuster 2001;Goldman-Rakic 1995). These findings highlight the need to understand how cortical persistent activity is used by downstream brain regions to influence behavior.

Prefrontal Activity Links Nonoverlapping Events in Memory

“…The predicted role of mPFC in this case is to maintain a representation of the CS across the trace interval so that it can converge with shock-related neuronal activity. Cue-triggered persistent firing of prefrontal neurons has been observed in a number of learning paradigms, including trace conditioning (Fuster, 1973;Baeg et al, 2001;Gilmartin and McEchron, 2005a;Siegel et al, 2012), and could provide this bridging signal. Our findings directly support this possibility by demonstrating that silencing PL during the trace interval, but not during the CS or between trials, impairs memory.…”

Classical eyeblink conditioning using electrical stimulation of caudal mPFC as conditioned stimulus is dependent on cerebellar interpositus nucleus in guinea pigs

“…There is a possibility that the mPFC activity which begins during the stimulation CS and persists beyond the stimulation CS offset to overlap with the US may induce long TEC successful establishment. Indeed, it is reported that the activity in the neurons of mPFC began during the tone CS and persisted to overlap with the US during TEC [77] .…”

Modification of persistent responses in medial prefrontal cortex during learning in trace eyeblink conditioning

“…delay cells; persistent activity; working memory PERSISTENT NEURAL RESPONSES, in which evoked spiking persists beyond stimulus offset, have been observed in the medial prefrontal cortex (mPFC) during tasks that impose a delay interval between stimulus presentation and behavioral response (Baeg et al 2001;Burgos-Robles et al 2009;Fritz et al 2010;Funahashi et al 1989;Fuster 1973;Fuster and Alexander 1971;Gilmartin and McEchron 2005;Gilmartin et al 2013;Hattori et al 2014;Kubota and Niki 1971;Siegel et al 2012). Persistent responses have been observed across stimulus modalities, including auditory (e.g., Baeg et al 2001;Gilmartin and McEchron 2005;Siegel et al 2012), visual (e.g., Funahashi et al 1989Fuster 1973;Miller et al 1996;Procyk and Goldman-Rakic 2006), and somatosensory (whisker stimulation; Hattori et al 2013). Such responses are considered to reflect the maintenance of a "memory trace" of that stimulus until a behavioral response can be made (Funahashi et al 1989;Fuster 1973;Goldman-Rakic 1995).…”

“…Recently, persistent responses have been reported in the mPFC during trace eyeblink conditioned responses (CRs), which require 200 -500ϩ training trials to acquire (Hattori et al 2014;Siegel et al 2012;Siegel and Mauk 2013;TakeharaNishiuchi and McNaughton 2008), providing a window of opportunity to examine the possible evolution of persistent responses early in learning. Trace conditioning consists of paired presentations of an initially neutral conditioned stimulus (CS; such as a tone or light) followed by a stimulus-free trace interval and terminating with a reflexive unconditioned stimulus (US; such as a puff of air to the eye; Fig.…”

“…Because the cerebellum requires near overlap of the CS and US to support learning (Chen et al 2014;Kalmbach et al 2010), the hypothesized role of the mPFC in trace conditioning is to provide a CS-evoked input to the cerebellum (via the pons) that persists across the stimulus-free trace interval to overlap with the US (Fig. 1A, bottom; Chen et al 2014;Kalmbach et al 2009;Siegel et al 2012;Weiss and Disterhoft 2011). To directly address whether persistent mPFC responses are acquired as a function of learning, single-unit activity was recorded in the mPFC of rabbits during trace eyeblink conditioning with an emphasis on examining the earliest phases of learning.…”