7 research outputs found
The Retrosplenial Cortex: Intrinsic Connectivity and Connections with the (Para)Hippocampal Region in the Rat. An Interactive Connectome
A connectome is an indispensable tool for brain researchers, since it quickly provides comprehensive knowledge of the brain's anatomical connections. Such knowledge lies at the basis of understanding network functions. Our first comprehensive and interactive account of brain connections comprised the rat hippocampalâparahippocampal network. We have now added all anatomical connections with the retrosplenial cortex (RSC) as well as the intrinsic connections of this region, because of the interesting functional overlap between these brain regions. The RSC is involved in a variety of cognitive tasks including memory, navigation, and prospective thinking, yet the exact role of the RSC and the functional differences between its subdivisions remain elusive. The connectome presented here may help to define this role by providing an unprecedented interactive and searchable overview of all connections within and between the rat RSC, parahippocampal region and hippocampal formation
Retrosplenial connectivity with the (para)hippocampal region
The hippocampal formation and parahippocampal region (HF-PHR) receives input from a variety of cortical and subcortical structures, and one of the cortical regions which are heavily interconnected with HF-PHR is the retrosplenial cortex (RSC; Wyss and Van Groen, 1992). RSC is known to be important for a number of cognitive functions, and in both rodents and humans the RSC contribution to visuospatial cognition and memory has recently been reviewed in detail (Vann et al., 2009; Ranganath and Ritchey, 2012). The similar functional attributes of RSC and HF-PHR and the dense connections between the regions suggest a relationship. However exactly which HF-PHR subdivisions are connected with which part of RSC, the topographies of the connections within these subregions and how information carried by these connections are integrated in the receiving subregion is unknown.
In this thesis I explored anatomical connections between HF-PHR and RSC at several levels. In the first part of the thesis all published anatomical tract-tracing experiments which comprise HF-PHR - RSC connections were reanalyzed. All reported projections within and between HF-PHR and RSC were presented in an interactive connectome.
In the second part I explored the synaptic organization and postsynaptic targets of one of these connections namely the projection originating in RSC and terminating in medial entorhinal cortex (MEC), a subregion within PHR. I showed that RSC projects densely to layer V of MEC, with very few fibers targeting layer III. An ultrastructural assessment of the synaptic complexes and optogenetic stimulation of these fibers in an in vitro slice preparation indicated that the majority of RSC synapses in MEC layer V are excitatory. I further identified the layer V neurons postsynaptic to these synapses. The electron microscopical data show a striking dominance of spines of putative principal neurons as targets for RSC inputs. Confocal data and optogenetic data indicate that among the postsynaptic targets are spiny principal cells which project to superficial layers of MEC.
In the third and fourth part I took a developmental approach to study how the interconnections between the two regions develop. To this end I used classical retro- and anterograde tracers injected in differently aged rats. The development of the anatomical connections and the development of the topographical distribution of these connections from postnatal day (P)1 to approximately P28 were characterized. I showed that developing RSC - HF-PHR interconnections are organized in a topographical manner, similar to the adult situation and that this topographical organization is present already when the first axons arrive their termination site.
I thus concluded that information from RSC may reach HF through pyramidal neurons in layer V of MEC which issue projections to the superficial layers of MEC. Neurons in the latter layers may relay information from RSC to HF since these layers harbor neurons projecting to HF. Alternative multisynaptic pathways connecting RSC via PHR to HF likely include RSC projections to postrhinal cortex and presubiculum. Both structures receive RSC inputs among others in superficial layers, which harbor neurons projecting to superficial layers of MEC. The early development of the reciprocal connections between RSC and HF-PHR, already at an early postnatal stage, before neurons are functionally differentiated, suggests that RSC-PHR interconnections are organized by experience independent mechanisms. This experience independent topographic organization suggests that RSC and HF-PHR are parts of one tightly coupled functional system and that RSC - HF-PHR interaction is necessary for proper functioning of the two regions
Postnatal development of retrosplenial projections to the parahippocampal region of the rat
The rat parahippocampal region (PHR) and retrosplenial cortex (RSC) are cortical areas important for spatial cognition. In PHR, head-direction cells are present before eye-opening, earliest detected in postnatal day (P)11 animals. Border cells have been recorded around eye-opening (P16), while grid cells do not obtain adult-like features until the fourth postnatal week. In view of these developmental time-lines, we aimed to explore when afferents originating in RSC arrive in PHR. To this end, we injected rats aged P0-P28 with anterograde tracers into RSC. First, we characterized the organization of RSC-PHR projections in postnatal rats and compared these results with data obtained in the adult. Second, we described the morphological development of axonal plexus in PHR. We conclude that the first arriving RSC-axons in PHR, present from P1 onwards, already show a topographical organization similar to that seen in adults, although the labeled plexus does not obtain adult-like densities until P12
Development and topographical organization of projections from the hippocampus and parahippocampus to the retrosplenial cortex
The rat hippocampal formation (HF), parahippocampal region (PHR), and retrosplenial cortex (RSC) play critical roles in spatial processing. These regions are interconnected, and functionally dependent. The neuronal networks mediating this reciprocal dependency are largely unknown. Establishing the developmental timing of network formation will help to understand the emergence of this dependency. We questioned whether the longârange outputs from HFâPHR to RSC in Long Evans rats develop during the same time periods as previously reported for the intrinsic HFâPHR connectivity and the projections from RSC to HFâPHR. The results of a series of retrograde and anterograde tracing experiments in rats of different postnatal ages show that the postnatal projections from HFâPHR to RSC display low densities around birth, but develop during the first postnatal week, reaching adultâlike densities around the time of eyeâopening. Developing projections display a topographical organization similar to adult projections. We conclude that the longârange projections from HFâPHR to RSC develop in parallel with the intrinsic circuitry of HFâPHR and the projections of RSC to HFâPHR
Integrating time from experience in the lateral entorhinal cortex
The encoding of time and its binding to events are crucial for episodic memory, but how these processes are carried out in hippocampalâentorhinal circuits is unclear. Here we show in freely foraging rats that temporal information is robustly encoded across time scales from seconds to hours within the overall population state of the lateral entorhinal cortex. Similarly pronounced encoding of time was not present in the medial entorhinal cortex or in hippocampal areas CA3âCA1. When animalsâ experiences were constrained by behavioural tasks to become similar across repeated trials, the encoding of temporal flow across trials was reduced, whereas the encoding of time relative to the start of trials was improved. The findings suggest that populations of lateral entorhinal cortex neurons represent time inherently through the encoding of experience. This representation of episodic time may be integrated with spatial inputs from the medial entorhinal cortex in the hippocampus, allowing the hippocampus to store a unified representation of what, where and when
Superficially projecting principal neurons in layer V of medial entorhinal cortex in the rat receive excitatory retrosplenial input
Principal cells in layer V of the medial entorhinal cortex (MEC) have a nodal position in the cortical-hippocampal network. They are the main recipients of hippocampal output and receive inputs from several cortical areas, including a prominent one from the retrosplenial cortex (RSC), likely targeting basal dendrites of layer V neurons. The latter project to extrahippocampal structures but also relay information to the superficial layers of MEC, closing the hippocampal-entorhinal loop. In the rat, we electrophysiologically and morphologically characterized RSC input intoMECand conclude that RSC provides an excitatory input to layerVpyramidal cells. Ultrastructural analyses of anterogradely labeled RSC projections showed that RSC axons in layer V of MEC form predominantly asymmetrical, likely excitatory, synapses on dendritic spines (90%) or shafts (8%), with 2% symmetrical, likely inhibitory, synapses on shafts and spines. The overall excitatory nature of the RSC input was confirmed by an optogenetic approach. Patterned laser stimulation of channelrhodopsin-expressing presynaptic RSC axons evoked exclusively EPSPs in recorded postsynaptic layer V cells. All responding layer V pyramidal cells had an axon extending toward the white matter. Half of these neurons also sent an axon to superficial layers. Confocal imaging of RSC synapses onto MEC layer V neurons shown to project superficially by way of retrogradely labeling from superficial layers confirmed that proximal dendrites of superficially projecting cells are among the targets of inputs from RSC. The excitatory RSC input thus interacts with both entorhinal-cortical and entorhinal-hippocampal circuits