Nucleus Reuniens Thalami Modulates Activity in Hippocampal Field CA1 Through Excitatory and Inhibitory Mechanisms
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The Journal of Neuroscience, July 15, 1997, 17(14):5640–5650 Nucleus Reuniens Thalami Modulates Activity in Hippocampal Field CA1 through Excitatory and Inhibitory Mechanisms M. J. Dolleman-Van der Weel,1,2 F. H. Lopes da Silva,2 and M. P. Witter1 1Graduate School for Neurosciences Amsterdam, Research Institute for Neurosciences, Faculty of Medicine, Department of Anatomy and Embryology, Vrije Universiteit, 1081 BT Amsterdam, The Netherlands, and 2Institute of Neurobiology, Faculty of Biology, University of Amsterdam, 1098 SM Amsterdam, The Netherlands The nucleus reuniens thalami (RE) originates dense projections extracellularly recorded units in strata oriens/alveus and distal to CA1, forming asymmetrical synapses on spines (50%) and radiatum, indicative of the activation of local interneurons. dendrites (50%). The hypothesis that RE input modulates trans- Thus, RE seems to modulate transmission in CA1 through a mission in CA1 through excitation of both pyramidal cells and (subthreshold) depolarization of pyramidal cells and a supra- interneurons was tested using electrophysiological methods in threshold excitation of putative inhibitory oriens/alveus and the anesthetized rat. The RE–CA1 afferents were selectively radiatum interneurons. stimulated at their origin; evoked field potentials and unit ac- RE-evoked monosynaptic or disynaptic field potentials were tivity were recorded in CA1. RE-evoked depth profiles showed associated with stimulation of rostral or caudal RE, respectively. a prominent negative deflection in the stratum lacunosum- Anatomically, a projection from caudal to rostral RE was dem- moleculare and a positive one in the stratum radiatum. The onstrated that can account for the disynaptic RE–CA1 input. lacunosum-moleculare sink–radiatum source configuration is Because caudal RE receives input from the hippocampus via compatible with RE-elicited depolarization of apical dendrites the subiculum, we propose the existence of a closed RE– of pyramidal cells. Despite a consistent and robust paired pulse hippocampal circuit that allows RE to modulate the activity in facilitation of RE-evoked field potentials, population spikes in CA1, depending on hippocampal output. the stratum pyramidale were not detected at any tested condi- Key words: rat; electrophysiology; neuroanatomical tracing; tion. This indicates the inability of RE–CA1 input to discharge hippocampus; midline thalamus; limbic system; learning and pyramidal cells. However, stimulation of RE-elicited spiking of memory The involvement of thalamic midline nuclei in early stages of physiological knowledge of RE is still lacking. A modulatory role Alzheimer’s disease (Braak and Braak, 1991, 1992) and in dience- for RE in normal functioning of the hippocampus has also been phalic amnesia (Rousseau, 1994) has recently drawn attention to suggested based on anatomical data (Wouterlood et al., 1990; the connectivity between the nucleus reuniens (RE) and structures Dolleman-Van der Weel and Witter, 1996). Within field CA1, RE of the medial temporal lobe (Herkenham, 1978; Wouterlood et al., fibers terminate in a dense laminar plexus confined to the stratum 1990; Dolleman-Van der Weel and Witter, 1996). In this study we lacunosum-moleculare (L-M) and form exclusively asymmetrical focused on the RE projection to hippocampal field CA1, a crucial (i.e., excitatory) synapses on spines (50%) and dendrites (50%) structure for learning and memory processes (Squire, 1992). (Wouterlood et al., 1990). These data indicate that RE fibers A few investigators have studied the contribution of RE to contact the spinous apical dendrites of pyramidal cells, as well as hippocampal functioning. Vanderwolf et al. (1985) examined the largely aspinous dendrites of interneurons. whether the medial thalamic nuclei, including RE, were involved Based on the latter anatomical observations and the findings by in generating hippocampal atropine-resistant theta rhythm. Their Hirayasu and Wada (1992a,b), we proposed that RE modulates extensive radiofrequency lesions, however, resulted in little or no transmission in CA1 through activation of both pyramidal and effect on this type of rhythmical activity. Hirayasu and Wada nonpyramidal cells. This hypothesis was tested using electrophys- (1992a,b) injected NMDA in the thalamic midline of the rat. iological methods to stimulate the RE–CA1 afferents selectively When NMDA was administered to RE, it caused tonic and/or in anesthetized rats. RE–CA1 fibers course mainly within the clonic generalized convulsions associated with temporal limbic inferior thalamic peduncle in a rostral direction, curve dorsally EEG seizure discharge. They proposed that RE participates in around the genu of the corpus callosum, and then run caudally via the modulation of temporal limbic excitability and seizure devel- the cingulate bundle (in which many hippocampal afferents and opment. Their findings suggest that RE influences the state of efferents course) to enter CA1 (Wouterlood et al., 1990). Within activity of the entorhinal–hippocampal circuit. Yet, basic electro- their terminal field in stratum L-M, RE axons overlap with the perforant path fibers from the entorhinal cortex (Herkenham, Received Feb. 27, 1997; revised May 8, 1997; accepted May 8, 1997. 1978; Wouterlood et al., 1990; Dolleman-Van der Weel et al., This work was supported by Neurowetenschappen Amsterdam Grant 90-20 from the Graduate School for Neurosciences Amsterdam. We thank Professor W. J. 1994). Thus, stimulation of RE–CA1 fibers neither in the cingu- Wadman for his advice and A. J. A. Juta for helping with the calculation of the CSDs. late bundle nor within their terminal field in stratum L-M can Correspondence should be addressed to Menno P. Witter, Department of Anat- provide the selectivity required. Therefore, the RE neurons had omy and Embryology, Faculty of Medicine, Vrije Universiteit, 7 van der Boechorst- straat, 1081 BT Amsterdam, The Netherlands. to be stimulated at their origin, and depth profiles of evoked field Copyright © 1997 Society for Neuroscience 0270-6474/97/175640-11$05.00/0 potentials and recordings of unit activity were performed in CA1. Dolleman-Van der Weel et al. • CA1 Responses to Stimulation of Nucleus Reuniens J. Neurosci., July 15, 1997, 17(14):5640–5650 5641 Our electrophysiological observations indicated the occurrence range of values. Therefore, we additionally examined whether early of monosynaptic and disynaptic RE–CA1 input. To substantiate (likely monosynaptic) and late (presumed disynaptic) responses showed a relationship with differences in recording or stimulation sites. Based on a possible intrinsic RE connectivity, which is likely to be involved histological analysis, we sorted the experiments with regard to: (1) the in disynaptically evoked CA1 responses, a neuroanatomical trac- site of recording in septal-to-temporal CA1, and (2) the site of stimula- ing method was used. tion in rostral-to-caudal RE. Subsequently, experiments were sorted according to latencies (early vs late) and then with respect to recording MATERIALS AND METHODS and stimulation sites. The application of paired stimuli provided the opportunity to study a We used 30 male Wistar rats (Harlan CPB, Zeist, The Netherlands), particular form of short term plasticity, termed paired pulse facilitation weighing 275–375 gm. Under halothane anesthesia the trachea was intu- (PPF). PPF was expressed numerically by the ratio between test response bated. The animal was then placed in a stereotaxic apparatus and amplitude/conditioning response amplitude and was calculated for elic- throughout the experiment artificially ventilated by a mixture of O and 2 ited field potentials at the synaptic level (stratum L-M). N O with 1% halothane. Body temperature was maintained using a 2 Whether stimulation of RE was sufficient to discharge pyramidal cells heating pad. The skull was exposed, and two burr holes were made on the and/or interneurons was further analyzed in extracellular recordings of left side of the brain to accommodate placement of stimulating and unit activity throughout the depth of field CA1. The latency of synaptic recording electrodes in RE and CA1, respectively. Because the most unit activity was measured as the time from the stimulus onset to the dorsal (i.e., septal) part of CA1 is less densely innervated by RE fibers moment of occurrence of the spike. Simultaneously recorded field po- than the ventral (temporal) part (Wouterlood et al., 1990), recordings tentials were averaged to provide the corresponding population response. were made approximately at the level of the splenium of the corpus Technical and theoretical considerations for current–source–density anal- callosum, or slightly more caudal (see Fig. 1A,B). Stereotaxic coordinates ysis. A one-dimensional current–source–density (CSD) analysis esti- were derived from Paxinos and Watson (1986). They were zeroed at mates the sites where currents flow into or out of the extracellular space bregma (Br.), the midline of the sinus, and the cortical (dura) surface during cellular activity (Freeman and Stone, 1969; Freeman and Nichol- [stimulation electrode in RE at an angle of 15° in the coronal plane: Br., son, 1975). Some theoretical and practical issues, however, have to be 21.80 mm; lateral (L), 2.0 mm; ventral (V), 7.0 mm; recording electrode taken into account. First, the recording should be in the plane of in CA1: Br., 25.6 mm; L, 4.3 mm; V, 1.6–3.1 mm, respectively]. To prevent the exposed brain tissue from drying, it was covered with warm maximal activation,