Nucleus reuniens of the midline thalamus: Link between the medial prefrontal cortex and the hippocampus

Abstract

The medial prefrontal cortex and the hippocampus serve well recognized roles in memory processing. The hippocampus projects densely to, and exerts strong excitatory actions on, the medial prefrontal cortex. Interestingly, the medial prefrontal cortex, in rats and other species, has no direct return projections to the hippocampus, and few projections to parahippocampal structures including the entorhinal cortex. It is well established that the nucleus reuniens of the midline thalamus is the major source of thalamic afferents to the hippocampus. Since the medial prefrontal cortex also distributes to nucleus reuniens, we examined medial prefrontal connections with populations of nucleus reuniens neurons projecting to hippocampus. We used a combined anterograde and retrograde tracing procedure at the light and electron microscopic levels. Specifically, we made Phaseolus vulgaris-leuccoagglutinin (PHA-L) injections into the medial prefrontal cortex and Fluorogold injections into the hippocampus (CA1/subiculum) and examined termination patterns of anterogradely PHA-L labeled fibers on retrogradely FG labeled cells of nucleus reuniens. At the light microscopic level, we showed that fibers from the medial prefrontal cortex form multiple putative synaptic contacts with dendrites of hippocampally projecting neurons throughout the extent of nucleus reuniens. At ultrastructural level, we showed that medial prefrontal cortical fibers form asymmetric contacts predominantly with dendritic shafts of hippocampally projecting reuniens cells. These findings indicate that nucleus reuniens represents a critical link between the medial prefrontal cortex and the hippocampus. We discuss the possibility that nucleus reuniens gates the flow of information between the medial prefrontal cortex and hippocampus dependent upon attentive/arousal states of the organism.

Introduction

The hippocampus and medial prefrontal cortex (mPFC) serve well recognized roles in memory processing [1], [2], [15], [16], [17], [20], [21], [22], [50], [54]. The hippocampus distributes heavily to the medial prefrontal cortex [12], [18], [28], [29], [31], [43], [47] and exerts strong excitatory actions on the mPFC [18], [30], [33], [34]. Despite the direct innervation/influence of the hippocampal formation (HF) on the mPFC, interestingly, there are no direct return projections from the mPFC to HF, and rather moderate mPFC projections to parahippocampal structures including the entorhinal cortex [6], [9], [27], [33], [37], [39], [40], [45], [49].

The nucleus reuniens (RE) of the ventral midline thalamus is the principal (or virtually sole) source of thalamic input to the hippocampus [8], [24], [42], [53], [55], [56], [57]. RE stimulation produces pronounced excitatory actions at CA1 of the hippocampus [7], [14]. Bertram and Zhang [7] compared the effects of stimulation of RE with stimulation of the CA3 region of the hippocampus on population responses (field EPSPs and spikes) at CA1, and reported that RE actions on CA1 were equivalent to, and in some cases considerably greater than, those of CA3 on CA1. They concluded that the RE projection to the hippocampus “allows for the direct and powerful excitation of the CA1 region. This thalamohippocampal connection bypasses the trisynaptic/commissural pathway that has been thought to be the exclusive excitatory drive to CA1.”

It has recently been shown [48], [49] that the mPFC, particularly the infralimbic (IL) and prelimbic (PL) cortices, distribute prominently to RE. The combined demonstration, then, that mPFC projects to RE and RE in turn to HF, suggests that RE may represent an important relay between the mPFC and hippocampus. It remains to be determined whether mPFC fibers distributing to RE contact RE neurons projecting to the hippocampus. To assess this, we made anterograde tracer injections (PHA-L) in the ventral mPFC and retrograde injections (Fluorogold) in the CA1/subiculum of HF and examined, at the light and ultrastructural level, synaptic connections of mPFC fibers on RE neurons projecting to the hippocampus. We showed that mPFC fibers form asymmetric (excitatory) contacts predominantly on dendritic shafts of RE cells projecting to HF. RE thus appears to be a critical link between the mPFC and HF, completing an important loop between these structures (HF → mPFC → RE → HF).