The Hippocampal Formation and Entorhinal Cortex

Located in the medial temporal lobe (see Figure 3.1 for a simplified illustration), the Hippocampal Formation (HF) is compartmented into several sub-areas [364]. The main sub-areas are considered to be the Dentate Gyrus (DG), Cornu Ammonis 3 (CA3), Cornu Ammonis 1 (CA1), as well as the subiculum, all of which contribute to spatial information processing [7, 364]. The small area between CA3 and CA1, Cornu Ammonis 2 (CA2), is under-represented in current hippocampal research and therefore its contribution to represent spatial information is not properly understood.

The Cornu Ammonis sub-fields are commonly called Hippocampus, and together with DG they form the Hippocampus proper [7].

Located adjacent to the Hippocampus lies the EC. Containing several spatially modulated neurons, it is considered one of the major inputs projecting to the Hippocampus and was one of the major areas of research during the last few years with respect to spatial information processing in the brain. It is subdivided into

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a medial and a lateral part, the Medial Entorhinal Cortex (mEC) and Lateral Entorhinal Cortex (lEC), respectively [7, 364].

There are currently two major lines of thought considering the general function-ality and purpose of the Hippocampus. On the one hand, it is attributed to episodic memory [229, 319, 358], i.e. the storage and retrieval of sequences of behaviorally relevant information [58, 107, 167, 364]. On the other hand, behavioral studies demon-strate its relation to space [125, 265, 383]. Here, it is perceived as the fundamental substrate for the biological equivalent of a navigational system [76, 249, 251], for mismatch correction of spatial knowledge [126], or generally speaking navigation and spatial memory consolidation [12, 167]. Important for spatial navigation, the network expresses one-shot learning capabilities [260].

Findings suggest that the DG plays a crucial role in mapping compressed inputs from the EC to a high-dimensional space. Thereby it decorrelates representations and performs pattern separation [210, 229, 239]. The objectives computed in CA1 and CA3 are primarily related to spatial and episodic memory [300, 357]. The precise functionality of most other sub-areas of the Hippocampus remain elusive. They express complexity both in organization as well as interaction and are attributed to declarative memory formation [364].

The inter-area connectivity including the Hippocampus and EC is considered to form a poly-synaptic circuit called trisynaptic loop [6] (see information-flow inlay in Figure 3.1). Local recurrent connections within the contained areas indicate additional nested loops of information processing [11]. The para-hippocampal region is organized and structured in six distinct layers, sharing similarities with the neocortex [50, 364, 386]. In contrast, the HF is organized in only three layers, namely the polymorphic or deep layer, a central layer, and a superficial layer. The perforant path is a unidirectional projection from EC to the Hippocampus, primarily to sub-areas DG, CA3, as well as CA1. Although the axons to CA3 origin mostly in layer II of the EC, several projections from layers III, V, and VI exist [386]. In contrast, the projections to CA1 origin mostly in layer II [364]. In the Hippocampus, the information flows mostly sequentially on unidirectional projections via mossy fibers from DG to CA3, and by Schaffer collaterals projecting onwards from CA3 to CA1 [107, 190]. In reverse, the Hippocampus back-projects to the EC.

Local recurrent connectivity suggests that CA3 forms an auto-associative memory [205, 241, 245, 277], likely in form of a CAN [356]. In contrast, CA1 presumably forms a hetero-associative memory [299, 386]. In addition to indirect excitatory recurrences, several direct recurrent connections or indirect couplings via inhibitory-interneurons were discovered in the Hippocampus and EC [115]. Curiously, the recurrent connectivity within mEC was found to be predominantly inhibitory [70].

The sub-areas of the Hippocampus are interconnected with multiple other areas in the rodent brain [7]. For instance, connections from and to the Pre-Frontal Cortex (PFC) exist and are necessary for spatial navigation [161, 284]. In turn, PFC is attributed to decision making and involved in the formation of long-term memories [102, 192, 284]. This suggests that PFC has the capability to govern the activity in the Hippocampus, e.g. by suppressing or facilitating specific neuronal responses which are related to the animal’s current desire [124]. Furthermore, connections towards and back-projections from the subiculum were reported [107]. The recurrent connectivity of hippocampal areas is considered to be essential for goal-directed navigation [179].

3.1 The Hippocampal Formation and Entorhinal Cortex 23

EC CA3

CA1 DG

CA1, CA3 EC

Figure 3.1 – Schematic of areas in the rodent brain and exemplary spike responses of place and grid cells. The main areas of interest in the rodent brain (yellow area) for spatial navigation are the Entorhinal Cortex, and Cornu Ammonis 1 and 3 (EC, CA1, and CA3; all highlighted in magenta). The information flows from the EC across the Dentate Gyrus (DG) to the CA3 and CA1 regions and recurrently back to the EC, forming thetrisynaptic loop. Single neuron recordings of pyramidal neurons from CA1 and CA3 mostly express a singular area of activity with respect to the location of the rat and are thus called place cells. The inlays show examples of typical cell responses in simulations in a circular environment for either CA1 and CA3, or EC. In contrast to place cells, stellate cells of the EC respond in regularly arranged locations and are calledgrid cells. In both examples, each gray dot represents a spike of a single neuron with respect to a circular arena.

LFPs recorded in the Hippocampus revealed an oscillation which is highly regular at a frequency of around 4−10 Hz while the animal is moving [48]. While the reason for this oscillation, termed Theta, is commonly attributed to network mechanisms, its true origin and purpose are not conclusively agreed upon. Observations suggest that the oscillation coordinates interactions between the Hippocampus, PFC, and other extra-hippocampal areas, thereby supporting decision processes and memory consolidation [140, 173]. The oscillation was also perceived to be important for short-term memory [366]. Furthermore, Theta is considered to be the result of neural activity traveling in form of waves and therefore a synchronization mechanism within the Hippocampus [221]. Theta oscillations were also discovered in the EC and thus linked to spatial memory formation [47], where it is considered to buffer temporal information, and separate retrieval and encoding of memories [140].

Neurons in the Hippocampus and the EC show activity which is temporally relative to Theta, an observation called Theta phase precession [169, 328]. When an animal is moving along a trajectory, the currently best matching place cell is spiking at the trough of Theta, while the place cells which correspond to places before (after) the current location are active on the upward (downward) slope of the oscillation.

Theta and Theta phase precession are illustrated in Figure 3.2. Likewise the Theta rhythm, this salient behavior is only partially understood and probably due to network mechanisms or other intrinsic dynamics [235]. Nevertheless, one of its main purposes is believed to form a compressed representation of temporal information [328]. Theta phase precession can thus be interpreted as the observable operation of a temporal buffer structure [188, 246]. Recently a link between Theta phase precession, spatial information, and reward modulation was suggested [362]. Interestingly, Theta phase precession of the Hippocampus was reported to be independent from Theta phase precession of the EC [134], indicating that it is either a general purpose mechanism or effect due to network dynamics, or corresponds to synchronization properties of afferent inputs [48, 173].

To summarize, the Hippocampus and EC are considered two major areas respon-sible for episodic memory, spatial navigation, and spatial information processing.

The flow of neural activity within and across the two areas forms several, potentially nested but distributed and concurrently operating, loops of information processing.