Differential involvement of prefrontal cortex, striatum, and hippocampus in DRL performance in mice

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Abstract

Behavioral effects of neurotoxic lesions of the hippocampus, medial prefrontal (prelimbic, infralimbic and anterior cingulate) cortex or dorsal striatum were assessed using a DRL-10s schedule in mice. Post-operative acquisition data indicate that mice with hippocampal, but not prefrontal or striatal lesions received fewer reinforcements during daily 30-min sessions, and were less efficient in the timing of their responses. Additional analysis of inter-response-time (IRT) distributions revealed that the responses of hippocampal-lesioned mice exhibited undistinguishable responses for short IRTs (up to 9s). In addition, prefrontal-lesioned mice demonstrated a degradation of performance with further testing, and a flattened IRT distribution at late test phase, while striatal-lesioned mice behaved similarly to sham-lesioned mice. These results are interpreted in terms of known functions of the hippocampus in behavioral inhibition, and of the prefrontal cortex in executive control/decision making (and time production).

Introduction

Identifying neural processes underlying time estimation is the focus of an active research community in cognitive neuroscience. Behavioral paradigms to assess timing processes and functions exist in the form of interval timing or peak procedure. In the simplest version of these tasks, each trial begins with the onset of a signal. The animal is free to respond at any time during the signal, but only the first response after a fixed delay is reinforced (discrete trial fixed-interval) (Church, 1984, Roberts, 1981). This and other similar tasks have been used to examine the critical roles played by the cortico-striatal pathway in time-regulated behaviors and time processing Review in Hinton and Meck, 2004, Lewis and Miall, 2006. The prefrontal cortex is considered to be important because of its apparent role in working memory and attention (Posner & Dehaene, 1994), while the striatum and dopaminergic system are thought to play a role of an internal clock.

Another procedure, termed “differential rate of low responding” schedule (DRL), presents a difference in that animal is required to withhold its responses until an imposed delay has passed, and any premature responses emitted before the time limit reset the delay. In this more “stringent” procedure, the performance and correct execution of the task might be strongly influenced by the capacity for behavioral inhibition, in addition to that for time estimation. A long-standing literature associates the integrity of the hippocampus and central cholinergic systems with DRL performance.

While a consensus exists that hippocampal lesions (Deacon, Reisel, Perry, & Rawlins, 2005; Sinden, Rawlins, Gray, & Jarrard, 1986), cholinergic dysfunctioning (Soffie & Lejeune, 1992), glutamatergic antagonists or other LTP blocking agents (Sanger, 1992, Tonkiss et al., 1988; Horwood, Ripley, & Stephens, 2004; Riesel et al., 2005) or aging (Soffie & Lejeune, 1991), all interfere with DRL performance, studies investigating directly the role of striatal and frontal regions in DRL performance are rare and/or nonexistent, especially for mouse species. Given the known importance of the prefrontal-striatal circuitry for timing functions, we might expect dramatic effects of lesions in these areas on acquisition and performance of DRL. Here, we report dissociable effects of lesions of the prefrontal (prelimbic, infralimbic and anterior cingulate) cortex and of the striatum on DRL schedule performance. Only prefrontal lesions produced significant deficits in DRL whose pattern is qualitatively and quantitatively distinct from those of hippocampal-lesioned mice.

Section snippets

Subjects

Subjects were 33 male mice of the C57Bl/6 J1Co strain (5–6 months old), obtained from Iffa/Credo (Lyon, France). Mice were housed 4–5 per cage during behavioral experiments, except during recovery from surgery, when they were housed individually for safe wound healing. They underwent a progressive water restriction regimen starting 3–4 days prior to the experiments, wherein they had limited access to water (30 min – 1 h per day). They were housed in a climate-controlled animal room (21–23 °C),

Histology

Histological analysis led to the rejection of one mouse from each of the PFC and HIP groups, due to an insufficient extent of lesions. The damage to the dorsal and ventral CA1 and CA3 regions of the hippocampus was nearly complete in the totality of HIP mice included in behavioral analyses, while in some animals the innermost portion of the DG was spared throughout the anterior–posterior extent of the hippocampus. Fig. 1 shows a representative case of HIP (A, B), PFC (D) and STR (E) lesions.

Discussion and conclusion

Our data confirm the well-established effects of hippocampal lesions in rats and in mice, and add new insight into the effects of prefrontal and striatal lesions on DRL performance. While the prefrontal cortex and striatum are both thought to be important for time estimation and processing, only prefrontal lesions resulted in performance deficits in DRL schedule. More precisely, while prefrontal lesions produced a quite normal response distribution at the early stage of test phase, their peak

Acknowledgments

Authors wish to thank to Roula Moussa, Sebastien Delcasso for behavioral test, and Angelique Faugere and Laurence Decorte for histology.

The work was supported by Alzheimer’s association, American Health Assistance Foundation, ACI: Integrative and Computational Neuroscience, France Alzheimer, Huntington’s disease society of America and Jerome Lejeune.

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